Tricyclic thromboxane A2 antagonists

ABSTRACT

Novel tricyclic compounds having a TXA 2  antagonizing activity represented by formula (I): ##STR1## possess a potent antagonizing action against thromboxane A 2  and also an antiallergic and/or antihistaminic activity, and are expected to have preventive and therapeutic effects on ischemic diseases, cerebro-vascular diseases, etc.

BACKGROUND OF THE INVENTION

The present invention relates to novel tricyclic compounds whichstrongly antagonize an action of thromboxane A₂ (hereafter referred toas TXA₂) and possess an antiallergic and/or antihistaminic activity.

It is hitherto known that TXA₂ strongly aggregates platelets and is apotent vasoconstrictor [cf. Arachidonic Acid Cascade and Drugs, editedby Shozo Yamamoto, Gendai Iryo Publishing Co., Ltd. (1985)]. FurtherTXA₂ is a powerful vasoconstrictor against bronchus and bronchial smoothmuscle. Therefore, TXA₂ is considered to take part in pathologicalconditions over a wide range. As examples, the following diseases can beexemplified.

(1) Ischemic disease

For example, myocardial infarction, angina pectoris, and thrombosis

(2) Cerebro-vascular disease

For example, transient ischemic attack, migraine, cerebral hemorrhage,and cerebral infarction

(3) Peripheral vascular diseases and disease caused by unbalanced lipidmetabolism

For example, atherosclerosis, capillary convulsion, peripheralcirculation disorders, hypertension, and pulmonary embolism

(4) Inflammatory and allergic disease

For example, bronchial asthma, bronchitis, pneumonia, nephritis, andhepatitis

(5) Shock

(6) Cancer metastasis

Accordingly, compounds that antagonize the action of TXA₂ are expectedto have therapeutic effects in preventing or treating one or more of thediseases described above or other diseases involving TXA₂. Furthermore,in those instances where use of a particular drug was limited due toside effects mediated by TXA₂ or considered to be mediated by TXA₂, itis expected to alleviate the side effects by the use of compounds whichantagonize the action of TXA₂.

In recent years, TXA₂ is also thought to play a role in the pathogenesisof allergic diseases, especially of an asthma [cf. J. Allergy Clin.Immunol., 77, 122 (1986); Arch. Pharmacol., 327, 148 (1984)].

As an antagonist of TXA₂, representative compounds are exemplified inThrombosis Research, 44, 377 (1986).

Furthermore, an indole compound having the following structure: ##STR2##and the like are disclosed in Japanese Published Unexamined PatentApplication No. 249960/1986 [West German Patent Application (DE) No.3,514,696] and a compound having the following structure: ##STR3## andthe like are disclosed in Japanese Published Unexamined PatentApplication No. 212552/1986 [West German Patent Application (DE) No.3,508,692]. These compounds have a phenylsulfonamide group as a sidechain and exhibit an activity of antagonizing TXA₂.

On the other hand, in tricyclic compounds represented by the followingformula: ##STR4## wherein R^(o) as a substituent on the aromatic ringhas carboxyl or a derivative thereof (for example, an ester, an amide,etc.; hereafter collectively referred to as carboxylic acid group)directly or via an alkylene chain, etc. and W^(o) is hydrogen or asubstituent such as oxo (═O), methylene (═CH₂), hydroxyl, alkoxyl, etc.,oxepine derivatives wherein X₁ -X₂ is --CH₂ O-- are known as showingantiinflammatory or antiallergic activities, etc. [J. Med. Chem., 19,941 (1976); ibid., 20, 1499 (1977); ibid, 21, 633 (1978); U.S. Pat. No.4,282,365 (Japanese Published Unexamined Patent Application No.21679/1983); U.S. Pat. No. 4,585,788; Japanese Published UnexaminedPatent Application Nos. 152673/1986; 152674/1986 and 152675/1986].

Further, it is also known that oxepine derivatives wherein R^(o) ishydrogen or a substituent other than the carboxylic acid group, such as,alkyl, alkoxyl, halogen, etc. and W^(o) has a (di)alkylaminoalkyl chainvia --S-- show antiasthmatic activities [Japanese Published UnexaminedPatent Application No. 126883/1983 (EP 0085870A)]. It is also known thatderivatives such as oxepine or thiepine (wherein X₁ -X₂ is --CH₂ S--)wherein W^(o) is alkylaminoalkylidene show an antidepressant action,etc. [U.S. Pat. Nos. 3,354,155 and 3,420,851; Drugs, 13, 161 (1977);Arz.-Forsch., 13, 1039 (1963); ibid., 14, 100 (1964)]. Furthermore, itis also known that derivatives such as cycloheptene (wherein X₁ -X₂ is--CH═CH--) or thiepine wherein W^(o) has an alkyl chain substituted withan alicyclic nitrogen-containing heterocyclic group such as piperazine,etc. at the terminal thereof via --NHCO-- are known to have a calciumantagonizing activity [Japanese Published Unexamined Patent ApplicationNos. 47466/1986 (EP 191867A) and 153280/1987].

Further oxepine derivatives having an antiallergic activity whereinR^(o) has a carboxylic acid group and W^(o) has a (di)alkylaminoalkylchain via --S-- are known [Japanese Published Unexamined PatentApplication Nos. 28972/1985 (U.S. Pat. No. 4,596,804); 152669/1986,152670/1986, 152671/1986 and 15672/1986 (all of them correspond to EP188802A); 152676/1986 and 257981/1986]. Furthermore, oxepine orcycloheptene (wherein X₁ -X₂ is --CH₂ CH₂ --) derivatives showing anantihistaminic activity wherein W^(o) is a (di)alkylaminoalkylidene areknown [Japanese Published Unexamined Patent Application No. 45557/1986(EP 214779A)]. Still further, oxepine derivatives wherein W^(o) is analkylidene substituted with an alicyclic nitrogen-containingheterocyclic group such as 4-methylpiperazinyl, 4-methylhomopiperazinyl,piperidino, pyrrolidinyl, thiomorpholino or morpholino or with a(di)alkyl-substituted amino at the terminal thereof are known as showingan antiallergic and antiinflammatory activity [Japanese PublishedUnexamined Patent Application No. 10784/1988 (EP 0235796A)].

Novel and useful TXA₂ antagonists are expected to have preventive andtherapeutic effects on various diseases, and are in demand. Furtherantiallergic agents having a TXA₂ -antagonizing activity are expected tohave preventive and therapeutic effects on allergic diseases, and are indemand.

SUMMARY OF THE INVENTION

An object of the present invention is to provide novel tricycliccompounds having a TXA₂ -antagonizing activity and antiallergic activityby containing both a carboxylic acid group as the foresaid R^(o), and,as the aforesaid W^(o), an alkylthio chain or alkylidene chainsubstituted at the terminal thereof with an alicyclicnitrogen-containing heterocyclic group having a substituent such asaryl, aralkyl, etc. thereon.

The present invention relates to a tricyclic compound [hereafterreferred to as Compound (I); compounds having other formula numbers arealso the same] represented by formula (I): ##STR5## wherein representssingle bond or double bond;

X₁ -X₂ represents --CH₂ O--, ##STR6## wherein l represents 0, 1 or 2,--CH₂ --CH₂ --, or --CH═CH--;

W represents --S-- or ═CH--;

n is 1, 2, 3, or 4;

one of R^(A) and R^(B) represents hydrogen and the other represents--Y--M wherein Y represents single bond, --CR¹ R² --(CH)_(m) --, or--CR¹ ═CR² --(CH₂)_(m) -- wherein each of R¹ and R² independentlyrepresents hydrogen or lower alkyl and m is 0, 1, 2, 3 or 4, in whichthe left side of each formula is bound to the mother nucleus; and Mrepresents --COOR³ wherein R³ represents hydrogen or lower alkyl,--CONR^(3a) R^(3b) wherein each of R^(3a) and R^(3b) independently hasthe same significances for R³ as described above, or tetrazolyl;

each of G^(A) and G^(B) independently represents lower alkyl, halogen,hydroxyl, or lower alkoxyl;

each of g^(A) and g^(B) independently represents 0, 1, 2 or 3;

Z represents >N--E¹ --Q wherein E¹ represents single bond, --CO--,--COO-- wherein the left side of the formula is bound to the nitrogenatom, or --SO₂ --; and Q represents optionally substituted aryl,optionally substituted aralkyl, optionally substituted aralkenyl,aromatic heterocyclic group, or ##STR7## wherein L represents hydrogen,hydroxyl, or lower alkoxy; E² represents single bond, --CO--, or##STR8## wherein R⁴ represents hydrogen or lower alkyl; and Q has thesame significance as described above; >C═CH--Q wherein Q has the samesignificance as described above; or ##STR9## p is 1, 2 or 3; and apharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

In the definition of Z in formula (I), the aryl is exemplified by phenyland naphthyl having 6 to 10 carbon atoms, etc.; the aralkyl isexemplified by benzyl, phenethyl, benzhydryl and trityl, etc. having 7to 20 carbon atoms, etc.; and the aralkenyl is exemplified by styryl andcinnamyl having 8 to 18 carbon atoms, etc. The substituent on each groupmeans independently 1 to 3 substituents on the aromatic ring andincludes a group selected from lower alkyl, halogen, trifluoromethyl,hydroxyl, lower alkoxyl and methylenedioxy formed together with theortho-position thereof. Likewise, the aromatic heterocyclic group shownby Q represents a group selected from furyl, thienyl, pyridyl,pyrimidinyl, quinolyl and isoquinolyl.

Further in the definition of each group in formula (I), the alkyl moietyin the lower alkyl and lower alkoxyl is a straight or branched alkylhaving 1 to 6 carbon atoms, for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl,hexyl, etc.; the halogen includes, for example, fluorine, chlorine,bromine and iodine.

The pharmaceutically acceptable salt of Compound (I) includes an acidaddition salt, a metal salt, an ammonium salt, an organic amine additionsalt, an amino acid addition salt, etc. which are pharmaceuticallyacceptable.

As the pharmaceutically acceptable acid addition salt of Compound (I),mention may be made of the inorganic acid salt such as hydrochloride,sulfate, phosphate, etc. and the organic acid salt such as acetate,malate, fumarate, tartarate, citrate, etc. As the pharmaceuticallyacceptable metal salt, the alkali metal salt such as sodium salt,potassium salt, etc.; alkaline earth metal salt such as magnesium salt,calcium salt, etc. and further the aluminum salt and the zinc salt areappropriate. As the ammonium salt, mention may be made of the salt ofammonium, tetramethylammonium, etc. As the pharmaceutically acceptableorganic amine addition salt, mention may be made of an addition salt ofmorpholine, piperidine, etc. As the pharmaceutically acceptable aminoacid addition salt, an addition salt of lysine, glycine, phenylalanineand the like are mentioned.

Hereafter processes for producing Compound (I) are described but theproduction of Compound (I) is not deemed to be limited thereto. Furtherin various processes, the reaction conditions can be appropriatelychosen from those described below.

The reaction solvent may be chosen from water or an organic solventwhich does not participate in the reaction and can be used alone or incombination. The organic solvent includes, for example, an alcohol suchas methanol, ethanol, propanol, isopropanol, etc.; an ether such asdiethyl ether, dioxane, tetrahydrofuran, ethylene glycol monomethylether, ethylene glycol dimethyl ether, etc.; a hydrocarbon such asbenzene, toluene, xylene, hexane, cyclohexane, petroleum ether, ligroin,decalin, etc.; a ketone such as acetone, methyl ethyl ketone, etc. anamide such as formamide, dimethylformamide, hexamethylphosphorictriamide, etc.; acetonitrile, ethyl acetate, dimethylsulfoxide,sulfolane or a halogenated hydrocarbon such as methylene chloride,dichloroethane, tetrachloroethane, chloroform or carbon tetrachloride,etc. Further in case that bases or acids later described are liquid,they may also be used as a solvent.

As the appropriate base, an inorganic or organic base can be used. Thesebases include an alkali metal hydroxide, for example, lithium hydroxide,sodium hydroxide or potassium hydroxide; an alkali metal carbonate, forexample, sodium carbonate, sodium hydrogencarbonate or potassiumcarbonate; an alkali metal acetate, for example, sodium acetate orpotassium acetate; an alkali metal alkoxide, for example, sodiummethoxide, sodium ethoxide or potassium tert-butoxide; or an organicmetal compound, for example, sodium hydride, n-butyl lithium, sec-butyllithium; and an organic amine, for example, triethylamine,tri-n-butylamine, pyridine, N,N-dimethylaminopyridine, picoline,lutidine, N,N-dimethylaniline, dicyclohexylmethylamine,N-methylpiperidine, morpholine, diazabicyclooctane, diazabicycloundeceneor N-benzyltrimethylammonium hydroxide (Triton B), etc.

As the appropriate acid, an inorganic or organic acid or Lewis acid canbe used. Examples of the inorganic acid include hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid,hypochloric acid, sulfurous acid or nitrous acid, etc. Examples of theorganic acid include formic acid, acetic acid, trifluoroacetic acid,benzoic acid, p-toluenesulfonic acid, camphorsulfonic acid ormethanesulfonic acid, etc. Examples of the Lewis acid include aluminumchloride, zinc chloride, tin chloride, boron trifluoride, borontrifluoride diethyl ether complex, titanium tetrachloride, etc.

The reaction temperature is generally from -80° C. to a boiling point ofa solvent. Heating without a solvent is also possible. The reaction maygenerally be carried out under normal pressure but it is also possibleto apply pressure. In this case, the reaction temperature may be raisedto a temperature higher than the boiling point of a solvent.

The reaction time is generally in a range of one minute to one week.

In the following description, preferred reaction conditions are given.

Further in the following description, the tricyclic moiety which doesnot directly participate in the reaction: ##STR10## wherein , X₁ -X₂,R^(A), R^(B), G^(A), G^(B), g^(A) and g^(B) have the same significancesas described above; is sometimes referred to as: ##STR11##

Compound (I) can be prepared from Compound (II) or from Compounds (IIIathrough d), etc. obtained from Compound (II) according to the followingreaction steps: ##STR12## wherein ##STR13## has the same significance asdescribed above; R⁵ represents lower alkyl, Hal represents halogen andPh represents phenyl.

Herein the halogen shown by Hal represents chlorine, bromine and iodineand the lower alkyl has the same significance as defined for the loweralkyl in each group in formula (I).

Compounds (II) are either described in J. Med. Chem., 19, 941 (1976);ibid., 21, 1035 (1978); ibid., 20, 1557 (1977); ibid., 20, 1499 (1977);ibid., 29, 2347 (1986); ibid., 21, 633 (1978); ibid., 20, 456 (1977);U.S. Pat. Nos. 4,172,949 and 4,282,365; Japanese Published UnexaminedPatent Application Nos. 21679/1983; 28972/1985; 152669/1986;152672/1986; 152673/1986; 152675/1986 and 10784/1988 etc. or can besynthesized according to methods described in these publications or in amanner similar thereto.

Moreover, Compounds (IIIa to d) can be synthesized from Compound (II)according to methods described in Japanese Published Unexamined PatentApplication Nos. 150083/1981; 28972/1985; 152670/1986; 152671/1986;152672/1986; 152675/1986 and 10784/1988, etc. or in a manner similarthereto.

Method 1-1 [Synthesis of Compound (Ia) in Compound (I), wherein W is--S-- (part 1)] ##STR14## wherein X₁ -X₂, R^(A), R^(B), G^(A), G^(B), Z,g^(A), g^(B), n and p have the same significances as described above.

Compound (Ia) can be obtained from Compounds (IIIa to c) and (IVa)according to the following reaction step: ##STR15## wherein A¹represents OH, OR⁵ or Hal; and ##STR16## Z, R⁵, Hal and p have the samesignificances as described above.

Compound (Ia) or acid addition salts thereof can be obtained by reactingCompound (IIIa) with 1 to 5 molar equivalents of an appropriatedehydration condensing agent, for example, trifluoroacetic anhydride atfrom 0° C. to room temperature for 1 to 24 hours in an inert solventsuch as methylene chloride, chloroform, etc., then adding 1 to 5 molarequivalents of Compound (IVa) or acid addition salts thereof (forexample, hydrochloride, hydrobromide, acetate, trifluoroacetate,p-toluenesulfonate, etc.; the same is applied hereafter) to the reactionsolution and carrying out the reaction at 0° C. to a boiling point ofthe solvent for 1 to 24 hours, if necessary, in the presence of anappropriate acid catalyst, for example, boron trifluoride diethyl ethercomplex.

Likewise, Compound (Ia) or acid addition salts thereof can be obtainedby reacting Compound (IIIb) with 1 to 5 molar equivalents of Compound(IVa) or acid addition salts thereof in an inert solvent such asmethylene chloride, chloroform, etc., at 0° C. to a boiling point of thesolvent for 1 to 24 hours, if necessary, in the presence of anappropriate acid catalyst, for example, boron trifluoride diethyl ethercomplex.

Furthermore, Compound (Ia) or acid addition salts thereof can beobtained by reacting Compound (IIIc) with 1 to 10 molar equivalents ofCompound (IVa) or acid addition salts thereof in an inert solvent suchas methylene chloride, chloroform, dimethylformamide, etc., at 0° C. toa boiling point of the solvent for 1 to 24 hours, if necessary, in thepresence of a base such as triethylamine, sodium hydride, etc.

Method 1-2 [Synthesis of Compound (Ia) (part 2)]

Likewise, Compound (Ia) can be obtained from Compounds (IIIa-c)according to the following reaction steps.

Firstly, Compound (VIb) or (VIc) is prepared from Compounds (IIIa-c)according to the following reaction steps: ##STR17## wherein ##STR18##A¹, Hal and n have the same significances as described above; and R⁶represents a group capable of being split as OR⁶.

Herein, R⁶ means, for example, alkylsulfonyl such as methanesulfonyl,trifluoromethanesulfonyl, etc. and arylsulfonyl such as phenylsulfonyl,p-toluenesulfonyl, etc.

The corresponding Compound (VIa) or (VIc) can be obtained by reactingCompound (IIIa) with 1 to 5 molar equivalents of an appropriatedehydrating and condensing agent, for example, trifluoroaceticanhydride, in an inert solvent such as methylene chloride, chloroform,etc., at a temperature of from 0° C. to room temperature for 1 to 24hours, then adding 1 to 10 molar equivalents of an alcohol (Va) or itshalide (Vb) to this reaction solution and carrying out the reaction at atemperature of between room temperature and at the boiling point of thesolvent, if necessary and desired, in the presence of an appropriateacid catalyst, for example, boron trifluoride diethyl ether complex, for1 to 24 hours.

Compound (VIa) or (VIc) can also be obtained by reacting Compound (IIIb)or (IIIc) with 1 to 10 molar equivalents of an alcohol (Va) or itshalide (Vb) in an inert solvent such as methylene chloride, chloroform,etc., at a temperature of between room temperature and the boiling pointof the solvent, if necessary and desired, in the presence of anappropriate acid catalyst, for example, boron trifluoride diethyl ethercomplex, or an appropriate base such as triethylamine for 1 to 24 hours.

Further the thus obtained Compound (VIa) may be reacted with 1 to 5molar equivalents of Hal-R⁶ or (R⁶)₂ O (wherein R⁶ and Hal have the samesignificances as described above) in an inert solvent such as methylenechloride, chloroform, etc., if necessary and desired, in the presence ofa base such as pyridine, etc., at a temperature of from -50° C. to roomtemperature for 1 to 24 hours to give Compound (VIb).

Furthermore, compound (VIa) may be reacted (1) with 1 to 5 molarequivalents of a halogenating agent, for example, thionyl chloride, inan inert solvent such as methylene chloride, chloroform, etc., ifnecessary and desired, in the presence of a base such as pyridine, etc.,at a temperature of from 0° C. to room temperature for 1 to 24 hours;(2) with 1 to 10 molar equivalents of an alkyl halide such as methyliodide in an inert solvent such as benzene in the presence of 1 to 10molar equivalents of triphenylphosphine and 1 to 10 molar equivalents ofdiethyl azodicarboxylate at a temperature of from -20° C. to a boilingpoint of the solvent for 1 to 24 hours; or (3) with 1 to 10 molarequivalents of a halogenating agent, for example, methanesulfonylchloride, in dimethylformamide in the presence of 1 to 10 molarequivalents of a base such as lithium chloride, etc., at a temperatureof from -20° to 100° C. for 1 to 24 hours, whereby Compound (VIc) isobtained.

Where Compound (VIc) is the chloride (Hal is Cl) or bromide (Hal is Br),the compound may be reacted further with an iodide, for example, sodiumiodide, in a polar solvent such as acetonitrile to give the iodide (Halis I). Compound (VIb) can be converted into Compound (VIc) under similarconditions.

Compound (VIb) or (VIc) can be converted into Compound (Ia) according tothe following reaction step: ##STR19## wherein A² represents OR⁶ or Hal;and R⁶, Hal, ##STR20## Z, p and n have the same significances asdescribed above.

Compound (Ia) can be obtained by reacting Compound (VIb) or Compound(VIc) with 1 to 10 molar equivalents of Compound (VII), if necessary, inthe presence of a molar equivalent to a largely excessive amount of abase such as sodium carbonate, triethylamine, pyridine, Triton B, sodiumhydride, etc., at a temperature of between room temperature and theboiling point of the solvent for 1 to 48 hours in an inert solvent suchas methylene chloride, chloroform, dichloroethane, dimethylformamide,dioxane, etc.

Further the reaction of Compound (VIc) with Compound (VII) may also becarried out in the presence of an iodide, for example, sodium iodide orpotassium iodide.

Method 2-1 [Synthesis of Compound (Ib) in Compound (I), wherein W is═CH-- (Part 1)] ##STR21## wherein X₁ -X₂, R^(A), R^(B), G^(A), G^(B), z,n, g^(A), g^(B) and p have the same significances as described above.

Compound (Ib) can be prepared according to the following reaction steps:##STR22## wherein ##STR23## Z, Ph, n and p have the same significance asdescribed above.

Firstly, a phosphonium salt (VIIIb): ##STR24## wherein Z, Hal, Ph, n andp have the same significances as described above, obtained by reactingtriphenylphosphine (Ph₃ P) with a halide: ##STR25## is treated with amolar equivalent of a base such as n-butyl lithium, etc. in an inertsolvent, for example, tetrahydrofuran, etc., at 0° C. to roomtemperature to give an ylide (VIIIa).

Compound (Ib) can be obtained by reacting 1 to 5 molar equivalents,based on Compound (II), of Compound (VIIIa), after or without isolation,with Compound (II) in an inert solvent, for example, tetrahydrofuran,etc., at a temperature of from 0° C. and a boiling point of the solvent.

Method 2-2 [Synthesis of Compound (Ib) (part 2)]

Compound (Ib) can also be obtained from Compound (II) according to thefollowing reaction steps: ##STR26## wherein ##STR27## Z, Hal, n and phave the same significances as described above.

Firstly, Compound (II) is reacted with 1 to 5 molar equivalents ofGrignard reagent (IVc) in an inert solvent such as tetrahydrofuran,diethyl ether, etc., at a temperature of from 0° C. to room temperature,for 1 to 48 hours to give an alcohol (IX).

Compound (IVc) can be obtained by reacting corresponding Compound (IVb)with 0.5 to 2 molar equivalents of magnesium in an inert solvent such astetrahydrofuran, diethyl ether, etc., if necessary and desired, in thepresence of a trace amount of iodine, at a temperature of from 0° C. toa boiling point of the solvent for 0.5 to 12 hours. The Grignard reagentthus formed is generally used in the following reaction withoutisolating the same.

The thus obtained Compound (IX) can be subjected to dehydration to giveCompound (Ib). For the dehydration, a method which comprises performingthe reaction in an inert solvent such as dioxane, etc., in the presenceof an acid, for example, p-toluenesulfonic acid, etc., at a temperatureof from room temperature to boiling point of the solvent for 1 to 12hours, or a method which comprises reacting with a halogenating agentsuch as thionyl chloride, etc., in an organic base such as pyridine,etc. at a temperature of from 0° C. to a boiling point of the solventfor 1 to 12 hours, or the like is adopted.

Method 2-3 [Synthesis of Compound (Ib) (part 3)]

Firstly, the carbonyl group of Compound (II) is converted into Compound(Xb) according to the following reaction steps: ##STR28## wherein##STR29## Ph and n have the same significances as described above, andR⁷ represents a hydroxyl-protecting group.

Herein, as the hydroxyl-protecting group, groups generally used asprotective groups for an alcoholic hydroxyl may be used. A preferredprotecting agent is, for example, tetrahydropyranyl or the like.

Firstly, an ylide (VIIIc) in which hydroxyl is protected by anappropriate protective group (for example, tetrahydropyranyl, etc.) isformed in an inert solvent, for example, tetrahydrofuran [J. Org. Chem.,44, 3760 (1979)].

Then, the formed ylide (VIIIc) is reacted with 0.2 to 1 molar equivalentof Compound (II) at a temperature of from -78° C. to the boiling pointof the solvent for 1 to 48 hours to give Compound (Xa).

Compound (Xa) can be converted into Compound (Xb) by removing theprotective group. The removal of protective group can be conducted in aconventional manner; in the case of using, for example,tetrahydropyranyl as a protective group, Compound (Xa) is treated withan acid catalyst such as p-toluenesulfonic acid, hydrochloric acid, etc.in a suitable hydrated solvent such as hydrated dioxane, hydratedtetrahydrofuran, etc., at a temperature of from 0° C. to the boilingpoint of the solvent for 1 to 24 hours to give Compound (Xb).

Compound (Xb) can be led to Compound (Ib) via Compound (Xc) or Compound(Xd) by the following reaction steps: ##STR30## wherein ##STR31## Z, R⁶,Hal, n and p have the same significances as described above.

The reactions can be performed in a manner similar to the method forleading from Compound (VIa) to Compound (Ia) described in Method 1-2.

Method 2-4 [Synthesis of Compound (IB-1) in Compound (Ib) wherein n is1] ##STR32## wherein X₁ -X₂, R^(A), R^(B), G^(A), G^(B), z, g^(A), g^(B)and p have the same significances as described above.

Compound (Ib-1) can be prepared according to the following reactionsteps: ##STR33## wherein ##STR34## Z, R⁶, Hal and p have the samesignificances as described above; [CH₂ O] represents formaldehyde and/ora polymer thereof; R^(8a) and R^(8b), which may be the same ordifferent, each represents lower alkyl or may be combined to nitrogenadjacent thereto to form a heterocyclic ring and R⁹ represents loweralkyl.

Herein, the lower alkyl in the definitions of R^(8a), R^(8b) and R⁹ hasthe same significance as described for the lower alkyl in formula (I).As the heterocyclic ring formed by R^(8a) and R^(8b), mention may bemade of pyrrolidine, piperidine, N-methylpiperazine, morpholine,thiomorpholine, N-methylhomopiperazine and the like.

Compound (IIId) is reacted with 1 to 10 molar equivalents offormaldehyde and/or a formaldehyde polymer, for example,paraformaldehyde, either in a hydrohalogenic acid, preferablyhydrochloric acid or in an inert solvent, for example, dioxane,saturated with hydrogen chloride and, if necessary and desired, in thepresence of a strong acid such as sulfuric acid or trifluoroacetic acid,at a temperature of from room temperature to the boiling point of thesolvent, for 1 to 24 hours to give Compound (Xd-1).

Further Compound (Xb-1) can be obtained under almost the same conditionsas described above except that no hydrohalogenic acid is added.

Furthermore, Compound (Xd-1) can also be obtained as follows. That is,Compound (IIId) is reacted with 1 to 2 molar equivalents of formaldehydeand/or a formaldehyde polymer, for example, paraformaldehyde, and 1 to 3molar equivalents of a secondary amine (XI) and trifluoroacetic acid, inan inert solvent such as methylene chloride, chloroform, dichloroethane,tetrachloroethane, etc., if necessary and desired, in the presence ofacetic acid, at a temperature of from room temperature to the boilingpoint of the solvent, for 1 to 48 hours to give Compound (Xe) or acidaddition salts thereof. Compound (Xe) can be led to Compound (Xd-1) byreacting with 1 to 10 molar equivalents of a halocarbonate, preferablyethyl chloroformate in an inert solvent such as methylene chloride,chloroform, dichloroethane, tetrachloroethane, etc., if necessary, inthe presence of the base such as triethyl amine and sodium acetatebetween at 0° C. and the boiling point of the solvent for 1 to 48 hours.

The thus obtained Compounds (Xb-1) and (Xd-1) can be converted intoCompound (Ib-1) as in the synthesis of Compound (Ib) from thecorresponding Compounds (Xb) and (Xd) described in Method 2-3.

Further Compound (Ib-1) can also be obtained according to the method forobtaining Compound (Xe) from Compound (IIId) in which Compound (VII) isused in place of Compound (XI).

Method 3 [Synthesis of Compound (Ic) in Compound (I), wherein Z is>N--E¹ --Q] ##STR35## wherein -, X₁ -X₂, R^(A), R^(B), G^(A), G^(B), W,E¹, Q, g^(A), g^(B), n and p have the same significances as describedabove.

Compound (Ic) can be prepared from Compounds (XII) and (XIII) obtainedin a manner similar to Methods 1 and 2 described above by the followingreaction steps: ##STR36## wherein W, E¹, Q, n and p have the samesignificances as described above and A³ represents a leaving group in--E¹ --Q.

Herein, in the case that E¹ is single bond, leaving group A³ representshalogen such as chlorine, bromine, iodine, etc. and in the case that E¹is --CO--, A³ --E¹ --Q represents HOOC--Q (A³ is OH) or a carboxylicacid reactive derivative. The carboxylic acid reactive derivativeincludes an acid halide (acid chloride, acid bromide, etc.), an acidanhydride (acid anhydride formed with a dehydrating condensing agentsuch as N,N'-dicyclohexylcarbodiimide, etc., in the reaction system,commercially available acid anhydrides, etc.), an activated ester(p-nitrophenyl ester, N-hydroxysuccinimide ester, etc.), a mixed acidanhydride (monoethyl carbonate, monoisobutyl carbonate, etc.) and thelike. Further in the case that E¹ is --COO--, A³ represents halogen asdescribed above and in the case that E¹ is --SO₂ --, A³ representshalogen or --O--SO₂ --Q.

Compound (Ic) can be obtained by reacting Compound (XII) or acidaddition salts thereof with 1 to 5 molar equivalents of Compound (XIII),either in an inert solvent such as methylene chloride, chloroform, etc.,in the presence of a base such as pyridine, etc., or in a basic organicsolvent such as pyridine or triethylamine, etc., at a temperature of 0°C. to room temperature for 1 to 24 hours.

Method 4-1 [Synthesis of Compound (Id) in Compound (I), wherein M is--COOH] ##STR37## wherein one of R^(A1) and R^(B1) represents --Y--COOHand the other represents hydrogen; and , X₁ -X₂, G^(A), G^(B), W, Z, Y,n, g^(A), g^(B) and p have the same significances as described above.

Compound (Id) can be obtained by hydrolysis of the correspondingcarboxylic acid ester.

That is, Compound (Id) can be obtained by subjecting Compound (Ie) [inCompound (I), compound wherein M is --COOR³ c (wherein R^(3c) representslower alkyl in the definitions for R³ described above)] synthesizedaccording to Methods 1 to 3, to an appropriate hydrolysis method, forexample, by reacting with a molar equivalent to an excess of sodiumhydroxide or potassium hydroxide, etc. in a solvent mixture of a loweralcohol such as methanol, ethanol, etc. and water, at a temperature offrom room temperature to the boiling point of the solvent for 1 to 48hours.

Method 4-2 [Synthesis of Compound (Id-1) in Compound (I), wherein Y issingle bond] ##STR38## wherein one of R^(A2) and R^(B2) represents--COOH and the other represents hydrogen; and , X₁ -X₂, G^(A), G^(B), W,Z, n, g^(A), g^(B) and p have the same significances as described above.

Compound (Id-1) can be obtained according to the following reactionsteps: ##STR39## wherein one of Hal^(A) and Hal^(B) represents Hal andthe other represents hydrogen; and , X₁ -X₂, R^(A2), R^(B2), G^(A),G^(B), W, Z, Hal, n, g^(A), g^(B) and p have the same significances asdescribed above.

Compound (Id-1) can be obtained by carboxylating Compound (XIV)synthesized from Compound (II-1) in a manner similar to Methods 1 to 3.

Carboxylation can be performed by reacting, for example, Compound (XIV)with 1 molar equivalent of a metallizing agent, e.g., n-butyl lithium,in an inert solvent such as tetrahydrofuran, etc., at a temperature offrom -78° C. to room temperature, for 10 minutes to 12 hours followed byreacting the resulting reaction mixture with 1 molar equivalent to alargely excessive amount of carbon dioxide at a temperature of from -78°C. to room temperature, for 10 minutes to 12 hours. Alternatively,Compound (Id-1) can be obtained by preparing the corresponding Grignardreagent from Compound (XIV) and magnesium in an inert solvent such asdiethyl ether, etc. in a manner similar to Method 2-2 and reacting thereagent with carbon dioxide, and the like method.

Method 5

In the methods for production shown by Methods 1 through 4, where groupsdefined in Compound (I) change under reaction conditions for practicingthe method or are inappropriate for practicing the method, the groupsmay be subjected to conventional means used in organic synthesischemistry, for example, means for protecting functional groups, meansfor removing protection, etc. [for example, cf., Green, ProtectiveGroups in Organic Synthesis, John Wiley & Sons Incorporated (1981)],methods for oxidation, reduction, hydrolysis, etc. [for example, cf.,SHIN-JIKKEN KAGAKU KOZA, vols. 14 & 15, Maruzen (1977)].

For example, in case that group M is --COOH, 4,4-dimethyloxazoline, etc.are preferably used as a protecting group for --COOH (for example,Japanese Published Unexamined Patent Application No. 10784/1988) in themethod in which the corresponding ester is hydrolyzed (cf. Method 4-1described above) or in the reaction using a Grignard reagent (cf., forexample, Method 2-2). Further, a desired compound can be obtained byhydrolyzing (removing a protecting group in) a compound obtained byMethods 1 through 4, etc. in which group --Y--M is --Y'--CH₂ OR¹⁰[wherein Y' represents a group obtained by removing CH₂ from Y and R¹⁰represents a protecting group for hydroxyl (e.g., acetyl,tetrahydropyranyl, etc.)] to convert into --Y'-CH₂ OH and oxidizing thecompound.

The intermediates and objective compounds in the respective methodsdescribed above can be isolated and purified by purification methodsconventionally used in organic synthesis chemistry, for example,filtration; extraction, washing, drying, concentration,recrystallization, various column chromatographies, etc. Further theintermediates may also be provided in the subsequent reaction, withoutbeing particularly purified.

In Compound (I) obtained by the foregoing methods, compounds wherein Wis shown by ═CH-- include geometrical isomers of E-form and Z-form withrespect to stereochemistry. In general, the methods described above givea mixture of these isomers. Isolation and purification-of these isomerscan be made in a conventional manner in organic synthesis chemistry, forexample, column chromatography, recrystallization, etc. It is alsopossible to isolate the isomers at stages of intermediates (Xa to Xe) bythe various methods described above.

Further, if desired, E- and Z-forms may be isomerized from each other.This can be made by treating each isomer under reflux in, e.g., aceticacid, for 1 to 24 hours, in the presence of an appropriate acid catalystsuch as p-toluenesulfonic acid, etc.

In the present invention, Compound (I) includes not only the E/Z isomersdescribed above but also all possible stereoisomers and a mixturethereof.

When the synthesis yields Compound (I) in the form of a salt and suchsalt is a desired product, the thus formed compound (I) may be purifiedas is.

When Compound (I) is obtained in a free form, salts may be formed in aconventional manner. Furthermore, Compound (I) and pharmaceuticallyacceptable salts thereof may also be present in the form of additionproducts to water or various solvents; these adducts including thepharmaceutically acceptable salts are also included in the presentinvention.

Specific examples of Compound (I) obtained by various methods are shownin Table 1.

Numbering of substitution positions in Table 1 and Table 6 laterdescribed does not necessarily harmonize with the correct nomenclature[cf. see (NOTE) below]; but for purpose of simplicity, numbering of thesubstitution positions is systematically made as illustrated below.##STR40##

In cycloheptene derivatives (wherein X₁ -X₂ is --CH₂ CH₂ -- or--CH═CH--), despite the positional number in the general formula above,for example, a substituent on the carbon at the 2-position in theformula above is correctly given as a substituent at the 3-position.However, in the tables, according to the positional numbering in theformula described above, --COOH on the carbon at the 2-position isindicated to be 2--COOH (correctly 3--COOH).

                                      TABLE 1                                     __________________________________________________________________________     ##STR41##                                                                     X.sub.1X.sub.2                                                                        ##STR42##                           R.sup.A /R.sup.B                                                                         Compound              __________________________________________________________________________                                                           No.                    CH.sub.2 O                                                                             ##STR43##                          2-COOCH.sub.3 2-COOH                                                                        1a 1b               "       "                                   2-CH.sub.2 COOCH.sub.3                                                                      2a                                                              2-CH.sub.2 COOH                                                                             2b                  "       "                                   2-CH.sub.2 CH.sub.2 COOCH.sub.                                                3             3a                                                              2-CH.sub.2 CH.sub.2 COOH                                                                    3b                  "       "                                   2-CH(CH.sub.3)COOCH.sub.3                                                                   4a                                                              2-CH(CH.sub.3)COOH                                                                          4b                  "       "                                                                                                                  ##STR44##    5                   "       "                                   3-COOCH.sub.3 6a                                                              3-COOH        6b                  "       "                                   9-COOCH.sub.3 7a                                                              9-COOH        7b                           ##STR45##                          2-COOCH.sub.3 2-COOH                                                                        8a 8b               "                                                                                      ##STR46##                          2-COOCH.sub.3 2-COOH                                                                        9a 9b               CH.sub.2 O                                                                             ##STR47##                          2-COOCH.sub.3 2-COOH                                                                        10a 10b             "                                                                                      ##STR48##                          2-COOCH.sub.3 2-COOH                                                                        11a 11b             "                                                                                      ##STR49##                          2-COOCH.sub.3 2-COOH                                                                        12a 12b             "       "                                   2-C(CH.sub.3).sub.2 COOCH.sub.                                                3             13a                                                             2-C(CH.sub.3).sub.2 COOH                                                                    13b                 "                                                                                      ##STR50##                           2-COOCH.sub.3 2-COOH                                                                       14a 14b             "                                                                                      ##STR51##                          2-COOCH.sub.3 2-COOH                                                                        15a 15b             "                                                                                      ##STR52##                          2-COOCH.sub.3 2-COOH                                                                        16a 16b             "                                                                                      ##STR53##                          2-COOCH.sub.3 2-COOH                                                                        17a 17b             "                                                                                      ##STR54##                          2-COOCH.sub.3 2-COOH                                                                        18a 18b             "                                                                                      ##STR55##                          2-COOCH.sub.3 2-COOH                                                                        19a 19b             "                                                                                      ##STR56##                          2-COOCH.sub.3 2-COOH                                                                        20a 20b             CH.sub.2 O                                                                             ##STR57##                          2-COOCH.sub.3 2-COOH                                                                        21a 21b             "                                                                                      ##STR58##                          2-COOCH.sub.3 2-COOH                                                                        22a 22b             "                                                                                      ##STR59##                          2-COOCH.sub.3 2-COOH                                                                        23a 23b             "                                                                                      ##STR60##                          2-COOCH.sub.3 2-COOH                                                                        24a 24b             "                                                                                      ##STR61##                          2-COOCH.sub.3 2-COOH                                                                        25a 25b             "                                                                                      ##STR62##                          2-COOCH.sub.3 26a 26b             "                                                                                      ##STR63##                          2-COOCH.sub.3 2-COOH                                                                        27a 27b             "                                                                                      ##STR64##                          2-COOCH.sub.3 2-COOH                                                                        28a 28b             "                                                                                      ##STR65##                          2-COOCH.sub.3 2-COOH                                                                        29a 29b             "                                                                                      ##STR66##                          2-COOCH.sub.3 2-COOH                                                                        30a 30b             "                                                                                      ##STR67##                          2-COOCH.sub.3 2-COOH                                                                        31a 31b             "                                                                                      ##STR68##                          2-COOCH.sub.3 2-COOH                                                                        32a 32b             CH.sub.2 O                                                                             ##STR69##                          2-COOCH.sub.3 2-COOH                                                                        33a 33b             "                                                                                      ##STR70##                          2-COOCH.sub.3 2-COOH                                                                        34a 34b             "                                                                                      ##STR71##                          2-COOCH.sub.3 2-COOH                                                                        35a 35b             "                                                                                      ##STR72##                          2-COOCH.sub.3 2-COOH                                                                        36a 36b             "                                                                                      ##STR73##                          2-COOCH.sub.3 2-COOH                                                                        37a 37b             "                                                                                      ##STR74##                          2-COOCH.sub.3 2-COOH                                                                        38a 38b             "       "                                   2-CH.sub.2 COOCH.sub.3                                                                      39a                                                             2-CH.sub.2 COOH                                                                             39b                 "       "                                   2-CH(CH.sub.3)COOCH.sub.3                                                                   40a                                                             2-CH(CH.sub.3)COOCH.sub.3                                                                   40b                 "       "                                   2-C(CH.sub.3).sub.2 COOCH.sub.                                                3             41a                                                             2-C(CH.sub.3).sub.2 COOH                                                                    41b                 "       "                                   2-CH.sub.2 CH.sub.2 COOCH.sub.                                                3             42a                                                             2-CH.sub.2 CH.sub.2 COOH                                                                    42b                 "                                                                                      ##STR75##                          2-COOCH.sub.3 2-COOH                                                                        43a 43b             "       "                                   2-C(CH.sub.3).sub.2 COOCH.sub.                                                3             44a                                                             2-C(CH.sub.3).sub.2 COOH                                                                    44b                 CH.sub.2 O                                                                             ##STR76##                          2-COOCH.sub.3 2-COOH                                                                        45a 45b             "                                                                                      ##STR77##                          2-COOCH.sub.3 2-COOH                                                                        46a 46b             "                                                                                      ##STR78##                          2-COOCH.sub.3 2-COOH                                                                        47a 47b             "       "                                   2-CH.sub.2 COOCH.sub.3                                                                      48a                                                             2-CH.sub.2 COOH                                                                             48b                 "       "                                   2-C(CH.sub.3).sub.2 COOCH.sub.                                                3             49a                                                             2-C(CH.sub.3).sub.2 COOH                                                                    49b                 "                                                                                      ##STR79##                          2-COOCH.sub.3 2-COOH                                                                        50a 50b             "                                                                                      ##STR80##                          2-COOCH.sub.3 2-COOH                                                                        51a 51b             "                                                                                      ##STR81##                          2-COOCH.sub.3 2-COOH                                                                        52a 52b             "                                                                                      ##STR82##                          2-COOCH.sub.3 2-COOH                                                                        53a 53b             "                                                                                      ##STR83##                          2-COOCH.sub.3 2-COOH                                                                        54a 54b             "                                                                                      ##STR84##                          2-COOCH.sub.3 2-COOH                                                                        55a 55b             "                                                                                      ##STR85##                          2-COOCH.sub.3 2-COOH                                                                        56a 56b              CH.sub.2 O                                                                            ##STR86##                          2-COOCH.sub.3 2-COOH                                                                        57a 57b             "                                                                                      ##STR87##                          2-COOCH.sub.3 2-COOH                                                                        58a 58b             "       "                                   2-C(CH.sub.3).sub.2 COOCH.sub.                                                3             59a                                                             2-C(CH.sub.3).sub.2 COOH                                                                    59b                 "                                                                                      ##STR88##                          2-COOCH.sub.3 2-COOH                                                                        60a 60b             "       "                                   2-CH.sub.3 COOCH.sub.3                                                                      61a                                                             2-CH.sub.2 COOH                                                                             61b                 "                                                                                      ##STR89##                          2-COOCH.sub.3 2-COOH                                                                        62a 62b             "       "                                   2-CH.sub.2 COOCH.sub.3                                                                      63a                                                             2-CH.sub.2 COOH                                                                             63b                 "       "                                   2-C(CH.sub.3).sub.2 COOCH.sub.                                                3             64a                                                             2-C(CH.sub.3).sub.2 COOH                                                                    64b                 "                                                                                      ##STR90##                          2-COOCH.sub.3 2-COOH                                                                        65a 65b             "       "                                   2-C(CH.sub.3).sub.2 COOCH.sub.                                                3             66a                                                             2-C(CH.sub.3).sub.2 COOH                                                                    66b                 "                                                                                      ##STR91##                          2-COOCH.sub.3 2-COOH                                                                        67a 67b             CH.sub.2 O                                                                             ##STR92##                          2-COOCH.sub.3 2-COOH                                                                        68a 68b             "                                                                                      ##STR93##                          2-COOCH.sub.3 2-COOH                                                                        69a 69b             "                                                                                      ##STR94##                          2-COOCH.sub.3 2-COOH                                                                        70a 70b             "                                                                                      ##STR95##                          2-COOCH.sub.3 2-COOH                                                                        71a 71b             "                                                                                      ##STR96##                          2-COOCH.sub.3 2-COOH                                                                        72a 72b             "                                                                                      ##STR97##                          2-COOCH.sub.3 2-COOH                                                                        73a 73b             "                                                                                      ##STR98##                          2-COOCH.sub.3 2-COOH                                                                        74a 74b             "                                                                                      ##STR99##                          2-COOCH.sub.3 2-COOH                                                                        75a 75b             "                                                                                      ##STR100##                         2-COOCH.sub.3 2-COOH                                                                        76a 76b             "                                                                                      ##STR101##                         2-COOCH.sub.3 2-COOH                                                                        77a 77b             "                                                                                      ##STR102##                         2-COOCH.sub.3 2-COOH                                                                        78a 78b             "                                                                                      ##STR103##                         2-COOCH.sub.3 2-COOH                                                                        79a 79b             CH.sub.2 O                                                                             ##STR104##                         2-CH.sub.2 COOCH.sub.3                                                        2-CH.sub.2 COOH                                                                             80a 80b             "       "                                   2-CH(CH.sub.3)COOCH.sub.3                                                                   81a                                                             2-CH(CH.sub.3)COOH                                                                          81b                 "       "                                   2-C(CH.sub.3).sub.2 COOCH.sub.                                                3             82a                                                             2-C(CH.sub.3).sub.2 COOH                                                                    82b                 "       "                                   2-CH.sub.2 CH.sub.2 COOCH.sub.                                                3             83a                                                             2-CH.sub.2 CH.sub.2 COOH                                                                    83b                 "                                                                                      ##STR105##                         2-COOCH.sub.3 2-COOH                                                                        84a 84b             "                                                                                      ##STR106##                         2-COOCH.sub.3 2-COOH                                                                        85a 85b             "       "                                   2-CH.sub.2 COOCH.sub.3                                                                      86a                                                             2-CH.sub.2 COOH                                                                             86b                 "       "                                   2-CH(CH.sub.3)COOCH.sub.3                                                                   87a                                                             2-CH(CH.sub.3)COOH                                                                          87b                 "       "                                   2-C(CH.sub.3).sub.2 COOCH.sub.                                                3             88a                                                             2-C(CH.sub.3).sub.2 COOH                                                                    88b                 "       "                                   2-CH.sub.2 CH.sub.2 COOCH.sub.                                                3             89a                                                             2-CH.sub.2 CH.sub.2 COOH                                                                    89b                 "                                                                                      ##STR107##                         2-COOCH.sub.3 2-COOH                                                                        90a 90b             "       "                                   2-C(CH.sub.3).sub.2 COOCH.sub.                                                3             91a                                                             2-C(CH.sub.3).sub.2 COOH                                                                    91b                 "                                                                                      ##STR108##                         2-COOCH.sub.3 2-COOH                                                                        92a 92b             CH.sub.2 O                                                                             ##STR109##                         2-COOCH.sub.3 2-COOH                                                                        93a 93b             "                                                                                      ##STR110##                         2-COOCH.sub.3 2-COOH                                                                        94a 94b             "                                                                                      ##STR111##                         2-COOCH.sub.3 2-COOH                                                                        95a 95b             "       "                                   2-CH.sub.2 COOCH.sub.3                                                                      96a                                                             2-CH.sub.2 COOH                                                                             96b                 "                                                                                      ##STR112##                         2-COOCH.sub.3 2-COOH                                                                        97a 97b             "       "                                   2-CH.sub.2 COOCH.sub.3                                                                      98a                                                             2-CH.sub.2 COOH                                                                             98b                 CH.sub.2 S                                                                             ##STR113##                         2-COOCH.sub.3 2-COOH                                                                        99a 99b             "                                                                                      ##STR114##                         2-COOCH.sub.3 2-COOH                                                                        100a 100b           CH.sub.2 CH.sub.2                                                                      ##STR115##                         2-COOCH.sub.3 2-COOH                                                                        101a 101b           "                                                                                      ##STR116##                         2-COOCH.sub.3 2-COOH                                                                        102a 102b           CHCH                                                                                   ##STR117##                         2-COOCH.sub.3 2-COOH                                                                        103a 103b           "                                                                                      ##STR118##                         2-COOCH.sub.3 2-COOH                                                                        104a 104b           __________________________________________________________________________

The thus prepared Compounds (I) exhibit a potent TXA₂ antagonizingactivity and some of them also possess an antiallergic activity and/orantihistaminic activity. Preferred examples of Compound (I) are shown inTable 2.

Names of the compounds given in Table 2, reference examples and exampleslater described are indicated by correct nomenclature.

                  TABLE 2                                                         ______________________________________                                        Compound                     No.                                              ______________________________________                                        11-[2-(4-Phenyl-1-piperazinyl)ethyl]thio-6,11-                                                             1b                                               dihydrodibenz[b,e]oxepin-2-carboxylic acid                                    11-[2-(4-Phenyl-1-piperazinyl)ethyl]thio-6,11-                                                             2b                                               dihydrodibenz[b,e]oxepin-2-acetic acid                                        11-[2-(4-Benzyl-1-piperazinyl)ethyl]thio-6,11-                                                             11b                                              dihydrodibenz[b,e]oxepin-2-carboxylic acid                                    11-[2-(4-Chlorobenzyl-1-piperazinyl)ethyl]thio-6,11-                                                       12b                                              dihydrodibenz[b,e]oxepin-2-carboxylic acid                                    2-Methyl-2-[11-[2-(4-chlorobenzyl-1-piperazinyl)-                                                          13b                                              ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-yl]-                               propionic acid                                                                11[2-[4-[Bis(4-fluorophenyl)methyl]-1-piperazinyl]-                                                        17b                                              ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-                                   carboxylic acid                                                               11-[2-(4-Benzyl-1-homopiperazinyl)ethyl]thio-6,11-                                                         32b                                              dihydrodibenz[b,e]oxepin-2-carboxylic acid                                    11-[2-(4-Phenyl-1-piperidinyl)ethyl]thio-6,11-                                                             37b                                              dihydrodibenz[b,e]oxepin-2-carboxylic acid                                    11-[2-(4-Benzyl-1-piperidinyl)ethyl]thio-6,11-                                                             38b                                              dihydrodibenz[b,e]oxepin-2-carboxylic acid                                    11-[2-(4-Benzyl-1-piperidinyl)ethyl]thio-6,11-                                                             39b                                              dihydrodibenz[b,e]oxepin-2-acetic acid                                        2-Methyl-2-[11-[2-(4-benzyl-1-piperidinyl)-                                                                41b                                              ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-yl]-                               propionic acid                                                                11-[2-[4-(4-Chlorobenzyl)-1-piperidinyl]ethyl]thio-6,11-                                                   43b                                              dihydrodibenz[b,e]oxepin-2-carboxylic acid                                    2-Methyl-2-[11-[2-[4-(4-chlorobenzyl-1-piperidinyl)-                                                       44b                                              ethyl[thio-6,11-dihydrodibenz[b,e]oxepin-2-yl]-                               propionic acid                                                                11-[2-[4-[2(3H)-Benzimidazolon-1-yl]piperidino]-                                                           47b                                              ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-                                   carboxylic acid                                                               11-[2-[4-[2(3H)-Benzimidazolon-1-yl]piperidino]-                                                           48b                                              ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-                                   acetic acid                                                                   2-Methyl-2-[11-[2-[4-[2(3H)-benzimidazolon-1-yl]-                                                          49b                                              piperidino]ethyl]thio-6,11-dihydrodibenz[b,e]-                                oxepin-2-carboxylic acid                                                      11-[2-[1-Phenyl-1,3,8-triazaspiro[4.5]decan-4-on-                                                          58b                                              8-yl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-                                2-carboxylic acid                                                             2-Methyl-2-[11-[2-[1-phenyl-1,3,8-triazaspiro[4.5]-                                                        59b                                              decan-4-one-8-yl]ethyl]thio-6,11-dihydrodibenz-                               [b,e]oxepin-2-yl]propionic acid                                               11-[3-(4-Benzyl-1-piperazinyl)propylidene]-6,11-                                                           62b                                              dihydrodibenz[b,e]oxepin-2-carboxylic acid                                    11-[3-(4-Benzyl-1-piperazinyl)propylidene]-6,11-                                                           63b                                              dihydrodibenz[b,e]oxepin-2-acetic acid                                        2-Methyl-2-[11-[3-(4-benzyl-1-piperazinyl)propylidene-                                                     64b                                              6,11-dihydrodibenz[b,e]oxepin-2-yl]propionic acid                             11-[3-[4-(4-Chlorobenzyl-1-piperazinyl)propylidene]-                                                       65b                                              6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid                               2-Methyl-2-[11-[3-[4-(4-chlorobenzyl-1-piperazinyl)-                                                       66b                                              propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-yl]-                             propionic acid                                                                11-[2-[4-(4-Thienylsulfonyl)-1-piperazinyl]-                                                               79b                                              ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic                        acid                                                                          11-[2-[4-(2-Thienylsulfonyl)-1-piperazinyl]-                                                               80b                                              ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic                            acid                                                                          2-[11-[2-[4-(2-Thienylsulfonyl)-1-piperazinyl]-                                                            81b                                              ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-yl]-                              propionic acid                                                                2-Methyl-2-[11-[2-[4-(2-thienylsulfonyl-1-                                                                 82b                                              piperazinyl)ethylidene-6,11-dihydrodibenz[b,e]oxepin-                         2-yl]propionic acid                                                           3-[11-[2-[4-(2-Thienylsulfonyl)-1-piperazinyl)-                                                            83b                                              ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-yl]-                              propionic acid                                                                11-[3-(4-Phenyl-1-piperidinyl)propylidene]-6,11-                                                           84b                                              dihydrodibenz[b,e]oxepin-2-carboxylic acid                                    11-[3-(4-Benzyl-1-piperidinyl)propylidene]-6,11-                                                           85b                                              dihydrodibenz[b,e]oxepin-2-carboxylic acid                                    11-[3-(4-Benzyl-1-piperidinyl)propylidene]-6,11-                                                           86b                                              dihydrodibenz[b,e]oxepin-2-acetic acid                                        2-Methyl-2-[11-[3-(4-benzyl-1-piperidinyl)-                                                                88b                                              propylidene]-6,11-dihydrodibenz[b,e] oxepin-2-yl]-                            propionic acid                                                                11-[3-[4-(4-Chlorobenzyl)-1-piperidinyl]propylidene]-                                                      90b                                              6,11-dihydrodibenz[b,e]oxepin-2-acetic acid                                   2-Methyl-2-[11-[3-[4-(4-chlorobenzyl-1-piperidinyl)-                                                       91b                                              propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-yl]-                             propionic acid                                                                11-[3-[4-[2(3H)-Benzimidazolon-1-yl]piperidino]-                                                           93b                                              propylidene[-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic                       acid                                                                          11-[2-[4-[2(3H)-Benzimidazolon-1-yl]piperidino]-                                                           98b                                              ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic                            acid                                                                          11-[2-(4-Benzyl-1-piperidinyl)ethyl]thio-6,11-                                                             99b                                              dihydrodibenzo[b,e]thiepin-2-carboxylic acid                                  11-[3-(4-Benzyl-1-piperidinyl)propylidene]-6,11-                                                           100b                                             dihydrodibenzo[b,e ]thiepin-2-carboxylic acid                                 5-[2-(4-Benzyl-1-piperidinyl)ethyl]thio-10,11-                                                             101b                                             dihydro-5H-dibenzo[a,d]cyclohepten-3-carboxylic acid                          5-[2-[4-(2-Thienyl)sulfonyl-1-piperidinyl)ethylidene]-                                                     102b                                             10,11-dihydro-5H-dibenzo[a,d]cyclohepten-3-carboxylic                         acid                                                                          5-[2-(4-Benzyl-1-piperidinyl)ethyl]thio-5H-dibenzo-                                                        103b                                             [a,d]cyclohepten-3-carboxylic acid                                            5-[2-[4-(2-Thienyl)sulfonyl-1-piperidinyl)ethylidene]-                                                     104b                                             5H-dibenzo[a,d]cyclohepten-3-carboxylic acid                                  ______________________________________                                    

Next, TXA₂ antagonizing activity of Compound (I) is described below.

Test on Anti-Platelet Activity (TXA₂ Antagonizing Test)

Using guinea pig platelets, influence of the compounds in accordancewith the present invention on platelet aggregation induced by U-46619(9,11-dideoxy-9α,11a-methanoepoxyprostaglandin F₂ α; manufactured byCayman Chemica Co., Ltd.) which is a TXA₂ /prostaglandin H₂ receptorstimulant was examined.

Male guinea pig (Hartley strain; body weight, 300 to 600 g) wasanesthesized by intraperitoneal administration of sodium pentobarbital(30 mg/kg) and blood was collected from the descending aorta of theabdomen with a 1/10 volume of sodium citrate. By centrifugation (KC-70:manufactured by Kubota Co., Ltd.) at 800 rpm for 10 minutes, plateletrich plasma (PRP) was collected. Platelet aggregation induced by U-46619(0.5-1 μM) was determined by photometry [Born, G.V.R. et al., Nature(London), 194, 927-929 (1962)]. A test compound was pretreated before 3minutes prior to aggregation induction and the ability of inhibitingaggregation was measured. The minimum concentration for inhibitingplatelet aggregation by 30% or more was defined as the minimum effectiveconcentration (MEC) of the test compound.

The results are shown in Table 3.

Antiallergic Activity Test

Antiallergic activity was examined in accordance with the passivecutaneous anaphylaxis (PCA) test using rats. As test animals, Wistarstrain male rats weighing 180 to 220 g were used to collect antiserumand for the PCA test, Wistar strain male rats weighing 120 to 140 g wereused.

(A) Preparation of anti-egg white albumin (EWA) rat serum

Anti-EWA rat serum was prepared according to the method of Stotland andShare [Can. J. Physiol. Pharmacol., 52, 1114 (1974)]. That is, 1 mg ofEWA was mixed with 20 mg of aluminum hydroxide gel and 0.5 ml ofpertussis-diphtheria-tetanus mixed vaccine. The mixture wassubcutaneously administered to the rat paw in 4 portions. Fourteen daysafter, blood was collected from the carotid artery and the serum wasisolated and stored in a state frozen at -80° C. Titer of this antiserumto homologous PCA for 48 hours was 1:32.

(B) Homologous PCA test for 48 hours using rats

Three rats were used per group. After the hair at the back was cut, 0.05ml each of anti-EWA rat serum diluted to 8-fold with physiologicalsaline was intracutaneously injected to each rat at the back in 2 placesto passively sensitize the rat. A test compound or its solution(physiological saline solution or CMC solution) was orally administered47 hours after and 0.5 ml/100 g of 1% Evans Blue physiological salinecontaining 2 mg of antigen EWA was then intravenously administered tothe tail vein an hour after the administration. Thirty minutes later,the animal was bled to death. The skin was peeled off and a leaked dyeamount at the blue dyed portion was measured according to the method ofKatayama et al. [Microbiol. Immunol., 22, 89 (1978)]. That is, the bluedyed portion was cut off with scissors, put into a test tube chargedwith 1 ml of 1 N potassium hydroxide and incubated at 37° C. for 24hours. After 9 ml of a mixture of 0.6 N phosphate : acetone (5:13) wasadded to the system, the mixture was shaken followed by centrifugationat 2500 rpm for 10 minutes. The absorbancy of the supernatant at 620 nmwas measured and the leaked dye amount was quantitatively determined bycomparison with a calibration curve previously prepared. A value of onerat was obtained from a mean value of the two portions and an inhibitionrate of each rat was calculated according to the following equation.##EQU1##

The case showing that the inhibition rate is 50% or more is judged to bepositive in the PCA inhibition activity and the minimum dose in which atleast one out of 3 rats was recognized to be positive was defined as theminimum effective dose (MED) of the test compound.

The results are shown in Table 3.

Acute Toxicity Test

Using three dd strain male mice weighing 20±1 g, a test compound wasorally (po; 300 mg/kg) or intraperitoneally (ip; 100 mg/kg)administered. MLD (the minimum lethal dose) was determined by observingthe mortality for seven days after administration.

The results are shown in Table 3.

                  TABLE 3                                                         ______________________________________                                                Acute Toxicity                                                                            Antiallergic                                                      (MLD)       Activity   TXA.sub.2 Antagonizing                         Compound                                                                              mg/kg       (MED) mg/kg                                                                              Activity (MEC)                                 No.**   po      ip      po       μg/ml                                     ______________________________________                                        1b'     >300    >100    10       3                                            8b      >300    >100    10       1                                            9b'     >300    >100    10       1                                            11b     >300    >100    10       1                                            25b     >300    >100    10       3                                            37b     >300    >100     1       10                                           38b     >300    >100     1       1                                            E-73b   >300    >100    >100     10                                           E-75b'  >300    >100    100      0.1                                          E-78b   >300    >100    >100     3                                            E-79b   >300    >100    >100     30                                           BM13177*                                                                              >300    >100    >100     3                                            (reference                                                                    compound)                                                                     ______________________________________                                         ##STR119##                                                                    **In Compound No., symbol ' indicates an addition product of the              corresponding compound in Tables 1 through 2 to a salt or solvent and,        symbols E and Z represents Eform and Zform, respectively (the same shall      apply hereinafter).                                                      

As demonstrated in Table 3, Compound (I) and pharmaceutically acceptablesalts thereof possess an excellent TXA₂ antagonizing activity and somecompounds also possess an antiallergic activity.

Binding study using ³ H-U46619 (TXA₂ Receptor Binding Activities Test)

Receptor binding was determined by a modified method of Kattelman et al.[Thrombosis Research, 41, 471 (1986)].

To a washed platelet suspension (1×10⁸ platelets) of guinea pig wereadded 12 nM of tritium-labeled U46619 (³ H-U46619; NEN Co., Ltd.) and atest compound (final concentration: 1 μM) solution. After keeping at 37°C. for 20 minutes, the mixture was rapidly filtered through a glassfiber filter paper (GF/C; Whatman). Immediately, the filter paper waswashed 5 times with 3 ml of ice-cold 50 mMTris-hydroxymethylaminomethane buffer (containing 100 mM sodiumchloride). The glass fiber filter was transferred to a vial and ascintillator (Ex-H; manufactured by Wako Pure Chemical Industries Co.,Ltd.) was added thereto. The radioactivity was determined with a liquidscintillation counter.

It is already known that ³ H-U46619 is capable of binding with TXA₂receptor (see the publication supra). An inhibitory activity of the testcompound against this binding means an ability of binding with the TXA₂receptor. It is also known that a good relationship exists between thisbinding activity and the anti-platelet activity (TXA₂ antagonizingtest).

An inhibitory activity (binding activity) of the test compound wascalculated by the following equation. ##EQU2##

The results are shown in Table 4.

                  TABLE 4                                                         ______________________________________                                                               % Inhibition                                           ______________________________________                                        Compound                                                                      No.                                                                           11b                      70                                                   25b                      78                                                   38b                      81                                                   E-73b                    85                                                   E-75b'                   85                                                   E-78b                    83                                                   E-79b                    77                                                   Reference compounds:                                                          Ketotifen                -3                                                   BM13177                  31                                                    ##STR120##              -4                                                    ##STR121##               1                                                   ______________________________________                                    

As demonstrated in Table 4, Compound (I) and pharmaceutically acceptablesalts thereof have an excellent binding ability to TXA₂ receptor.

This inhibitory activity is not observed with hitherto knownantiallergic agents, for example, Ketotifen [Merck Index, 10th edition,page 762 (1983)] and known antiallergic agents such as Compound (A)(Japanese Published Unexamined Patent Application No. 28972/1985) andCompound (B) (Japanese Published Unexamined Patent Application No.10784/1988); one of excellent activity of Compound (I) is TXA₂ receptorbinding ability.

Binding study using ³ H-Pyrilamine (Histamine H₁ receptor binding)

Receptor binding was determined by the method of chang et al. [J.Neurochem., 32, 1953 (1979)].

The cerebellum of guinea pig was suspended in a 40-fold mount (V/W) ofchilled 50 mM phosphate buffer (pH 7.5) with Polytron Homogenizer(Kinematica Co., Ltd.). The suspension was centrifuged (35,500×g, 10minutes). The resulting precipitates were resuspended in an equal amountof fresh buffer followed by centrifugation. A 100-fold amount v/W) ofchilled buffer was added to the final precipitates.

To 1 ml of the membrane suspension adjusted as described above wereadded 50 μl of tritium-labeled pyrilamine (³ H-pyrilamine; NEN Co.,Ltd.) and 50 μl of a test compound. The mixture was allowed to stand at25° C. for 30 minutes, 4 ml of chilled buffer was added thereto. Themixture was rapidly filtered through a glass fiber filter (GF/C;Whatman). The filter paper was further washed three times with 5 ml ofbuffer. Hereafter procedures were performed in a manner similar to theTXA₂ receptor binding test to determine radioactivity.

An inhibitory activity of the test compound against H₁ receptor wascalculated by the following equation. ##EQU3##

The amount bound in the presence of a test compound is an amount of ³H-pyrilamine-bound radioactivity in the presence of a test compound invarious concentrations.

Inhibitory activity of the test compounds at 10⁻⁶ M are shown in table5.

                  TABLE 5                                                         ______________________________________                                                        (%) Inhibition                                                ______________________________________                                        Compound                                                                      No.                                                                           1b'               68                                                          11b               95                                                          25b               95                                                          38b               92                                                          Reference Compounds:                                                          Ketotifen         100                                                         BM13177            0                                                          Compound A        88                                                          ______________________________________                                    

Compound (I) and pharmaceutically acceptable salts thereof may beadministered alone but in general, it is preferably administered asvarious medical preparation. These medical preparations are used foranimal and human beings.

The medical preparation in accordance with the present invention maycontain, as an active ingredient, Compound (I) or pharmaceuticallyacceptable salts thereof singly or as admixture with other optionaleffective components for different treatment. Further these medicalpreparations can be produced by optional procedures well known in thepharmaceutical field, by mixing the active ingredient together with oneor more pharmaceutically acceptable carriers.

Herein, as the optional effective components for different treatmentcombined with Compound (I) or pharmaceutically acceptable salts thereof,mention may be made of, for example, a steroid, a non-steroidantiinflammatory agent, a peripheral analgesic, a leucotrieneantagonist, a leucotriene biosynthesis inhibitor, an H₂ receptorantagonist, an antihistaminic agent, a histamine release inhibitor, abronchodilator, an angiotensin converting enzyme inhibitor, athromboxane A₂ biosynthesis inhibitor, an H⁺ -K⁺ ATPase inhibitor, acoronary dilator, a calcium antagonist, a diuretic, a xanthine oxidaseinhibitor, a cerebral circulation improving agent, a celebral metabolismactivator, a cerebral protecting agent, a liver protecting agent, anantiplatelet agent, a thrombolytic agent, an adrenaline α receptorantagonist, an adrenergic β receptor agent, an adrenaline β receptorantagonist, a serotonine antagonist, a platelet activation factor (PAF)antagonist, an adenosine receptor antagonist, an antihyperlipidemicagent, a cholesterol biosynthesis inhibitor, an immunostimulating agent,an immunosuppressive agent, an anticancer agent, etc.

It is preferred that the most effective route for treatment be selectedas a route for administration. Oral or parenteral administration such asintrarectal, topical, intranasal, intraocular, intrabuccal,subcutaneous, intramuscular and, intravenous routes, etc. are mentioned.

As the form of administration, prepartions of the invention may beadministered as a capsule, a tablet, a granule, a powder, a syrup, anemulsion, a suppository, an ointment, an eyedrop, a nosedrop, a troche,an aerosol, an injection, etc.

A liquid preparation suited for oral administration, for example, anemulsion and a syrup can be prepared using water; sugars such assucrose, sorbitol, fructose, etc.; glycols such as polyethylene glycol,propylene glycol, etc.; oils such as sesame oil, olive oil, soybean oil,etc.; antiseptics such as a p-hydroxybenzoic acid ester, etc.; flavorssuch as strawberry flavor, pepper mint, etc. Further a capsule, atablet, a powder and a granule, etc. can be prepared using an excipientsuch as lactose, glucose, sucrose, mannitol, etc.; a disintegrator suchas starch, sodium alginate, etc.; a lubricant such as magnesiumstearate, talc, etc.; a binder such as polyvinyl alcohol, hydroxypropylcellulose, gelatin, etc.; a surfactant such as an aliphatic ester, etc.;a plasticizer such as glycerine, etc.

A preparation suited for parenteral administration is composed of asterile aqueous preparation containing, active compounds which arepreferably isotonic to the blood of the recipient. For example, with aninjection, a solution for injection is prepared using carriers composedof a saline solution, a glucose solution or a mixture of saline waterand glucose solution.

A nasal spray preparation is composed of a purified aqueous solution ofthe active compounds which contains an antiseptic and an isotonic agent.Such a preparation is adjusted to pH compatible with the nasal membraneand to an isotonic state.

An ocular preparation is prepared in a manner similar to the nasalspray, except that pH and isotonic factors are controlled so as to fitthose of eyes.

A topical preparation is prepared by dissolving or suspending the activecompound in one or more media, for example, a mineral oil, petroleum, apolyvalent alcohol or other bases used for topical medical preparations.

A preparation for rectal administration is provided as a suppositoryusing conventional carriers, for example, cacao fat, hydrogenated fat orhydrogenated fat carboxylic acid, etc.

Further these parenteral preparations may also be added with one or moreauxiliary components such as a diluent, a fragrance, an antiseptic(including an antioxidant), an excipient, a disintegrator, a lubricant,a binder, a surfactant, a plasticizer and the like.

Effective dose and regimen of administration of Compound (I) orpharmaceutically acceptable salts thereof vary depending upon mode ofadministration, age and body weight of the patient and properties orseverity of conditions to be treated. In which may be administered as asingle or divided doses.

Hereafter, the present invention is described by referring to ReferenceExamples and Examples below.

Intermediates obtained in the following Reference Examples are shown inTable 6.

                                      TABLE 6                                     __________________________________________________________________________     ##STR122##                                                                   Compound                                                                      (Reference                                                                    Example)                                                                            X.sub.1 -X.sub.2                                                                       R.sup.o     X.sup.o                                            __________________________________________________________________________    a (1) CH.sub.2 O                                                                             2-COOCH.sub.3                                                                           O                                                    b (2) "        "         OH                                                   c (3) "        "         CHCH.sub.2 Cl                                        d (4) "        2-CH.sub.2 COOCH.sub.3                                                                  O                                                    e (5) "        "         CHCH.sub.2 Cl                                        f (6) "        2-C(CH.sub.3).sub.2 COOCH.sub.3                                                         O                                                    g (7) "        "         OH                                                   h (8) "        2-COOCH.sub.3                                                                            ##STR123##                                          i (9) "        "                                                                                        ##STR124##                                          j (10)                                                                              "        "                                                                                        ##STR125##                                          k (11)                                                                              "        "                                                                                        ##STR126##                                          l (12)                                                                              "        2-C(CH.sub.3).sub.2 COOCH.sub.3                                                          ##STR127##                                          m (13)                                                                              CH.sub.2 O                                                                             2-C(CH.sub.3).sub.2 COOCH.sub.3                                                          ##STR128##                                          n (14)                                                                              "        "                                                                                        ##STR129##                                          o (15)                                                                              CH.sub.2CH.sub.2                                                                       2-COOCH.sub.3                                                                            ##STR130##                                          p (16)                                                                              "        "                                                                                        ##STR131##                                          q (17)                                                                              CHCH     "                                                                                        ##STR132##                                          r (18)                                                                              "        "                                                                                        ##STR133##                                          s (19)                                                                              CH.sub.2 O                                                                             "                                                                                        ##STR134##                                          t (20)                                                                              "        "         CHCH.sub.2 CH.sub.2 OSO.sub.2 CH.sub.3               u (21)                                                                              "        "                                                                                        ##STR135##                                          __________________________________________________________________________

Reference Example 1 Methyl11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound a)

A mixture of 348.9 g of methyl p-hydroxybenzoate sodium salt, 402.4 g ofphthalide and 200 g of sodium chloride was stirred at 150° C. for 6hours. After completion of the reaction, the reaction mixture was cooledto room temperature and 4 liters of 10% acetic acid aqueous solutionwere added thereto. The mixture was allowed to stand at room temperatureovernight. After stirring at room temperature for 3 hours, crystals wererecovered by filtration. To the crystals was added 6 liters of water.After stirring at room temperature for 30 minutes, the crystals weretaken out by filtration. To the crystals was added 3 liters of toluene.The mixture was stirred at room temperature for an hour. The crystalswere taken out by filtration and dried by heating under reduced pressureto give 393.9 g of 2-(4-methoxycarbonylphenoxy)methyl benzoate.

IR (KBr tablet, cm⁻¹): 3400, 1700, 1610, 1260, 1235

In 5.0 liters of methylene chloride was suspended 392.7 g of the thusobtained 2-(4-methoxycarbonylphenoxy)methyl benzoate and, 266.0 g oftrifluoroacetic anhydride was added to the suspension. After stirring atroom temperature for an hour, 19.4 g of boron trifluoride ethyl ethercomplex was added to the mixture followed by stirring at roomtemperature for 2 hours. The reaction solution was poured into icewater. After fractionation, the organic phase was washed with a dilutedsodium hydroxide aqueous solution and then with water, dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theconcentrate was recrystallized from isopropyl ether to obtain 335.3 g ofthe objective compound as white crystals.

Melting point: 128°-129° C.

    ______________________________________                                        Elemental analysis: as C.sub.16 H.sub.12 O.sub.4                                             C    H                                                         ______________________________________                                        Found (%)        71.55  4.48                                                  Calcd. (%)       71.63  4.51                                                  ______________________________________                                    

NMR (CDCl₃, δ, ppm): 3.84(s, 3H), 5.14(s, 2H), 6.87-8.93(m, 7H)

IR (KBr tablet, cm⁻¹) 1710, 1650, 1610, 1250, 1010

Reference Example 2 Methyl11-hydroxy-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound b)

Compound as 50 g, obtained in Reference Example 1 was suspended in 300ml of methanol and 6.3 g of sodium borohydride was added to thesuspension. The mixture was stirred at room temperature for 2 hours.After completion of the reaction, 10 ml of acetic acid and 300 ml ofwater were added thereto followed by stirring for 30 minutes. Insolublematters were taken out by filtration and washed with methanol and thenwith water. By drying with heating under reduced pressure, 40 g of theobjective compound was obtained.

NMR (CDCl₃, δ, ppm): 2.16(s, 6H), 2.30-2.76(m, 4H), 3.83(s, 3H), 4.83and 6.40(ABq, J=12.6Hz, 2H), 5.01(s, 1H), 6.79-7.93(m, 7H)

IR (neat, cm⁻¹): 2950, 1710, 1240, 1015

Reference Example 3 Methyl(E)-11-(2-chloroethylidene)-6,11-dihydrodibenz-[b,e]-oxepin-2-carboxylate(Compound c)

4-Methylpiperazine, 30 ml, and 74 g of paraformaldehyde were dissolvedin 2 l of tetrachloroethane and 100 ml of trifluoroacetic acid wasdropwise added to the solution. After stirring at 60° C. for 2 hours, asolution of 36 g of methyl11-methylene-6,11-dihydrodibenz[b,e]-oxepin-2-carboxylate in 600 ml oftetrachloroethane was dropwise added to the reaction mixture followed bystirring at 90° C. for further 3 hours. The reaction mixture wasconcentrated to dryness under reduced pressure and 4 N hydrochloric acidaqueous solution was added to the residue to adjust pH to 1. Then, themixture was washed with diethyl ether. Thereafter, 10 N sodium hydroxideaqueous solution was added to adjust pH to 13. Extraction was performedwith 3 l of methylene chloride. After washing with saturated sodiumchloride aqueous solution and drying over anhydrous sodium sulfate, thesolvent was distilled off under reduced pressure. The resulting residuewas subjected to silica gel column chromatography (eluent; hexane:ethylacetate:triethylamine=5:5:1) to give 44 g of methyl11-[2-(4-methyl-1-piperazinyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylateas colorless oil.

MS (m/z): 378 (M⁺)

NMR (CDCl₃, δ, ppm): 2.24(s, 3H), 2.45(s, 8H), 2.94-3.32(m, 2H), 3.84(s,3H), 5.22(bs, 2H), 5.85 and 6.22(t, J=6.8Hz, 1H), 6.66-8.07(m, 7H)

E-form compound, 21.5 g, isolated from the Z/E mixture described abovein a conventional manner and 23.5 g of sodium acetate were suspended in250 ml of dichloroethane and, 27.1 ml of ethyl chloroformate wasdropwise added to the suspension. After completion of the dropwiseaddition, the mixture was stirred at room temperature for an hour andthe solvent was distilled off under reduced pressure. The residue wasextracted with 400 ml of ethyl acetate. After washing with saturatedsodium chloride aqueous solution and drying over anhydrous sodiumsulfate, the solvent was distilled off under reduced pressure. Theobtained crude product was recrystallized from isopropanol to give 14.3g of the objective compound as white crystals.

Melting point: 134°-135° C.

    ______________________________________                                        Elemental analysis: as C.sub.18 H.sub.15 ClO.sub.3                                           C    H                                                         ______________________________________                                        Found (%)        68.55  4.77                                                  Calcd. (%)       68.68  4.80                                                  ______________________________________                                    

NMR (CDCl₃, δ, ppm): 3.90(s, 3H), 4.16(d, J=8.1 Hz,

2H), 4.88(bs, 1H), 5.57(bs, 1H), 6.31(t, J=8.1 Hz, 1H), 6.79-8.04(m, 7H)

Reference Example 4 Methyl11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetate (Compound d)

The corresponding starting material was used, treated in a mannersimilar to Reference Example 1 and recrystallized from methanol to givethe objective compound as light yellow crystals.

Melting point: 75°-76° C.

Reference Example 5 Methyl(E)-11-(2-chloroethylidene)-6,11-dihydrodibenz[b,e]-oxepin-2-acetate(Compound e)

The corresponding starting material was used, treated in a mannersimilar to Reference Example 3 and recrystallized from isopropanol togive the objective compound as white crystals.

Melting point: 127°-128° C.

    ______________________________________                                        Elemental analysis: as C.sub.19 H.sub.17 ClO.sub.3                                           C    H                                                         ______________________________________                                        Found (%)        69.37  5.40                                                  Calcd. (%)       69.41  5.21                                                  ______________________________________                                    

NMR (CDCl₃, δ, ppm): 3.55(s, 2H), 3.69(s, 3H), 4.14 (d, J=8.1 Hz, 2H),4.7-5.4(m, 2H), 6.23(t, J=8.1 Hz, 1H), 6.74(d, J=8.1 Hz, 1H),6.95-7.4(m, 6H)

IR (KBr tablet, cm⁻¹): 1731, 1487, 1256, 1137, 1004

REFERNCE EXAMPLE 6 Methyl2-methyl-2-[(11-oxo-6,11-dihydrodibenz[b,e]oxepin)-2-yl]propionate(Compound f)

Compound d, 30 g, obtained in Reference Example 4 was suspended in 300ml of dimethylformamide and 30 g of potassium hydroxide as powder andthen 27 ml of methyl iodide were added to the suspension. The mixturewas stirred at room temperature for 2 hours. The solvent was distilledoff under reduced pressure and the residue was extracted with 500 ml ofethyl acetate. The extract was washed successively with saturated sodiumbicarbonate aqueous solution and saturated sodium chloride aqueoussolution. After drying over anhydrous magnesium sulfate, the solvent wasdistilled off under reduced pressure. The obtained residue was subjectedto silica gel column chromatography (eluent; hexane:ethyl acetate=10:1)for purification to give 3.6 g of the objective compound as colorlessoil.

NMR (CDCl₃, δ, ppm): 1.62(s, 6H), 3.66(s, 3H), 5.17 (s, 2H), 7.01(d,J=8.8 Hz, 1H), 7.2-7.9(m, 5H), 8.22(d, J=2.6 Hz, 1H)

IR (neat, cm⁻¹): 2874, 1729, 1648, 1597, 1490, 1016

REFERENCE EXAMPLE 7 Methyl2-methyl-2-[(11-hydroxy-6,11-dihydrodibenz[b,e]oxepin)-2-yl]propionate(Compound g)

The objective compound was obtained as colorless oil from Compound fobtained in Reference Example 6 in a manner similar to Reference Example2.

NMR (CDCl₃, δ, ppm): 1.56(s, 6H), 3.62(s, 3H), 4.97 and 5.90(ABq, J=13.1Hz, 2H), 5.61(s, 1H), 6.87 (d, J=8.4 Hz, 1H), 7.05-7.40(m, 6H)

IR (neat, cm⁻¹): 2974, 1728, 1497, 1010

REFERENCE EXAMPLE 8 Methyl11-(2-hydroxyethyl)thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound h):

In 400 ml of methylene chloride was suspended 40.0 g of Compound bobtained in Reference Example 2. Trifluoroacetic anhydride, 21.0 ml, wasadded to the suspension followed by stirring at room temperature for anhour. Then, 10.7 ml of 2-mercaptoethanol was added to the mixturefollowed by stirring for an additional 4 hours. After 100 ml ofmethylene chloride was added to the reaction mixture, the mixture waswashed with saturated aqueous sodium chloride solution. After dryingover anhydrous magnesium sulfate, the solvent was distilled off underreduced pressure. The obtained crude product was recrystallized fromtoluene to give 37.6 g of the objective compound as white crystals.

Melting point: 128°-130° C.

    ______________________________________                                        Elemental analysis: as C.sub.18 H.sub.18 O.sub.4 S                                           C    H                                                         ______________________________________                                        Found (%)        65.26  5.55                                                  Calcd. (%)       65.43  5.49                                                  ______________________________________                                    

NMR (CDCl₃, δ, ppm): 2.66(dt, J=2.1, 6.0 Hz, 2H) (t, J=5.9 Hz, 2H),3.89(s, 3H), 4.91 and 6.43(ABq, J=12.7 Hz, 2H), 5.09(s, 1H),6.82-7.98(m, 7H)

IR (KBr tablet, cm⁻¹): 3420, 1708, 1683, 1610, 1437, 1318, 1008

REFERENCE EXAMPLE 9 Methyl11-(2-chloroethyl)thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound i):

Compound h, 20.0 g, obtained in Reference Example 8 was dissolved in 200ml of dimethylformamide and, 12 ml of 2,4,6-cholidine and 4.0 g oflithium chloride were added to the solution. Under ice cooling, 5.4 mlof methanesulfonyl chloride was dropwise added to the mixture. Afterstirring at room temperature overnight, the solvent was distilled offunder reduced pressure. The residue was extracted with ethyl acetate.The extract was washed successively with 1N hydrochloric acid aqueoussolution and saturated sodium chloride aqueous solution. After dryingover anhydrous magnesium sulfate, the solvent was distilled off underreduced pressure. The obtained residue was purified by silica gel columnchromatography (eluent; hexane:ethyl acetate=5:1) and crystallized fromhexane to give 20.8 g of the objective compound.

Melting point: 100°-102° C.

    ______________________________________                                        Elemental analysis: as C.sub.18 H.sub.17 ClO.sub.3 S                                         C    H                                                         ______________________________________                                        Found (%)        61.77  4.80                                                  Calcd. (%)       61.97  4.91                                                  ______________________________________                                    

NMR (CDCl₃, δ, ppm): 2.54-3.62(m, 4H), 3.84(s, 3H), 5.04(s, 1H), 4.87and 6.37(ABq, J=13.2 Hz, 2H), 6.76-8.12(m, 7H)

IR (CHCl₃, cm⁻¹): 1714, 1611, 1322, 1295, 1132, 1008

REFERENCE EXAMPLE 10 Methyl11-(2-iodoethyl)thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound j)

Compound i, 10.1 g, obtained in Reference Example 9 was dissolved in 150ml of acetonitrile and, 14.6 g of sodium iodide was added to thesolution. The mixture was heated under reflux for 5 hours. Afterallowing it to stand for cooling, the reaction mixture was extractedwith ethyl acetate and the extract was washed twice with saturatedsodium chloride aqueous solution. After drying over anhydrous magnesiumsulfate, the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent;hexane:ethyl acetate=10:1) and further solidified with hexane to give3.1 g of the objective compound as white solid.

Melting point: 111°-113° C.

    ______________________________________                                        Elemental analysis: as C.sub.18 H.sub.17 IO.sub.3 S                                          C    H                                                         ______________________________________                                        Found (%)        49.08  3.71                                                  Calcd. (%)       49.10  3.89                                                  ______________________________________                                    

NMR (CDCl₃, δ, ppm): 2.68-3.22(m, 4H), 3.88(s, 3H), 5.09(s, 1H), 4.91and 6.37(ABq, J=13.2 Hz, 2H), 6.78-8.08(m, 7H)

IR (CHCl₃, cm⁻¹): 1714, 1611, 1295, 1120, 1008

REFERENCE EXAMPLE 11 Methyl[2-(1-piperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound k)

Compound j, 7.0 g, obtained in Reference Example 10 and 6.8 g ofpiperazine were heated under reflux for 8 hours in 300 ml of ethanol.The solvent was distilled off under reduced pressure. 4N hydrochloricacid aqueous solution was added to the residue to adjust pH to 3followed by washing with diethyl ether. Next, 10 N sodium hydroxideaqueous solution was added to adjust pH to 13. Extraction was performedwith 500 ml of ethyl acetate. After washing successively with saturatedsodium bicarbonate aqueous solution and saturated sodium chlorideaqueous solution, the extract was dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure to give 5.9 g ofthe objective compound as light yellow oil. The product was provided forthe following reaction without further purification.

NMR (CDCl₃, δ, ppm): 2.19-3.33(m, 12H), 3.84(s, 3H), 5.06(s, 1H), 4.86and 6.44(ABq, J=12.7 Hz, 2H), 6.76-8.12(m, 7H)

MS (m/Z): 402 (M⁺)

REFERENCE EXAMPLE 12 Methyl2-methyl-2-[11-(2-hydroxyethyl)thio-6,11-dihydrodibenz[b,e]oxepin]-2-yl]propionate(Compound ():

The objective compound was obtained as colorless oil in a manner similarto Reference Example 8 using Compound g obtained in Reference Example 7.

NMR (CDCl₃, δ, ppm): 1.56(s, 6H), 2.64(dt, J=2.2, 6.0 Hz, 2H), 3.65(s,3H), 4.85 and 6.27(ABq, J=13.1 Hz, 2H), 5.01(s, 1H), 6.7-7.4(m, 7H)

REFERENCE EXAMPLE 13 Methyl2-methyl-2-[[11-(2-chloroethyl)thio-6,11-dihydrodibenz[b,e]oxepin]-2-yl]propionate(Compound m)

The objective compound was obtained as colorless oil in a manner similarto Reference Example 9 using Compound l obtained in Reference Example12.

NMR (CDCl₃, δ, ppm): 1.57(s, 6H), 2.6-2.9(m, 2H), 3.2-3.4(m, 2H),3.65(s, 3H), 4.85 and 6.23(ABq, J=13.1 Hz, 2H), 5.04(s, 1H), 6.7-7.4(m,7H)

REFERENCE EXAMPLE 14 Methyl2-methyl-2-[[11-(2-iodoethyl)thio-6,11-dihydrodibenz[b,e]oxepin]-2-yl]propionate(Compound n)

The objective compound was obtained as colorless oil in a manner similarto Reference Example 10 using Compound m obtained in Reference Example13.

NMR (CDCl₃, δ, ppm): 1.56(s, 6H), 3.64(s, 3H), 5.27 (s, 1H)

REFERENCE EXAMPLE 15 Methyl5-(2-hydroxyethyl)thio-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-3-carboxylate(Compound o)

In 15.3 ml of methylene chloride was suspended 0.51 g of methyl5-hydroxy-10,11-dihydro-5N-dibenzo[a,d]-cyclohepten-3-carboxylate. Underice cooling, 0.27 ml of trifluoroacetic anhydride was added to thesuspension followed by stirring at room temperature for an hour. Then,0.14 ml of 2-mercaptoethanol was added to the mixture followed bystirring for further an hour. After 10 ml of methylene chloride wasadded to the reaction mixture, the mixture was washed with saturatedaqueous sodium chloride solution. After drying over anhydrous magnesiumsulfate, the solvent was distilled off under reduced pressure. Theobtained residue was purified by silica gel column chromatography(eluent; hexane:ethyl acetate=1:1) and recrystallized from toluene togive 0.51 g of the objective compound as light yellow crystals.

Melting point: 107°-109° C.

NMR (CDCl₃, δ, ppm): 2.51-2.65(m, 3H), 2.75-3.03(m, 2H), 3.56-3.98(m,4H), 3.87(s, 3H), 5.16(s, 1H), 7.14-7.25(m, 5H), 7.82(dd, J=1.5, 7.9 Hz,1H), 7.91(s, 1H)

REFERENCE EXAMPLE 16 Methyl5-(2-iodoethyl)thio-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-3-carboxylate(Compound p)

Compound o, 0.46 g, obtained in Reference Example 15 and 1.10 g oftriphenyl phosphine were suspended in 9.2 ml of benzene. While stirringunder ice cooling, 0.65 ml of diethyl azodicarboxylate was added to thesuspension followed by stirring at room temperature for 10 minutes.Then, 0.26 ml of iodomethane was added to the mixture followed bystirring at room temperature for 30 minutes. After 10 ml of ethylacetate and 10 ml of water were added thereto, the mixture was extractedwith ethyl acetate. The extract was washed with saturated aqueous sodiumchloride solution. After drying over anhydrous magnesium sulfate, thesolvent was distilled off under reduced pressure. The obtained residuewas purified by silica gel column chromatography (eluent; hexane:ethylacetate=3:1) to give 0.57 g of the objective compound as pale yellowoil.

NMR (CDCl₃, δ, ppm): 2.70-3.08(m, 6H), 3.63-3.81(m, 2H), 3.89(s, 3H),5.17(s, 1H), 7.17-7.32(m, 5H), 7.84(dd, J=1.7, 7.8 Hz, 1H), 7.92(s, 1H)

REFERENCE EXAMPLE 17 Methyl5-(2-hydroxyethyl)thio-5H-dibenzo[a,d]cyclohepten-3-carboxylate(Compound q)

The corresponding starting material was used, treated in a mannersimilar to Reference Example 15 and recrystallized from toluene to givethe objective compound as pale yellow crystals.

Melting point: 130°-132° C.

NMR (CDCl₃, δ, ppm): 2.30-2.50(m, 3H), 3.51(t, J=6.2 Hz, 2H), 3.89(s,3H), 5.31(s, 1H), 7.00(s, 1H), 7.02(s, 1H), 7.09-7.41(m, 5H), 7.91(dd,J=1.5, 7.9 Hz, 1H), 8.01(s, 1H)

REFERENCE EXAMPLE 18 Methyl5-(2-iodoethyl)thio-5H-dibenzo[a,d]cyclohepten-3-carboxylate (Compoundr)

Compound q obtained in Reference Example 17 was used and treated in amanner similar to Reference Example 16 to give the objective compound aspale yellow oil.

NMR (CDCl₃, δ, ppm): 2.57-3.07(m, 4H), 3.92(s, 3H), 5.31(s, 1H), 7.01(s,1H), 7.02(s, 1H), 7.09-7.41 (m, 5H), 7.91(dd, J=1.5, 7.9 Hz, 1H),8.01(s, 1H)

REFERENCE EXAMPLE 19 Methyl(E)-11-[2-(1-piperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-acetate(Compound s)

The objective compound was obtained as colorless oil from Compound c(E-form) obtained in Reference Example 3 in a manner similar toReference Example 11.

NMR (CDCl₃, δ, ppm): 1.95-3.0(m, 7H), 3.10(d, J=7.0 Hz, 2H), 3.83(s,3H), 4.75-5.5(m, 2H), 6.20(t, J=7.0 Hz, 1H), 6.71(d, J=8.5 Hz, 1H),6.95-7.45(m, 4H), 7.73(dd, J=2.2, 8.5 Hz, 1H), 7.99(d, J=2.2 Hz, 1H)

REFERENCE EXAMPLE 20 Methyl(E,Z)-11-[3-(methylsulfonyl)oxy]propylidene-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound t)

[3-[(Tetrahydro-2H-pyran-2-yl)oxy]propyl]triphenylphosphonium bromide,40.0 g, was suspended in 250 ml of tetrahydrofuran. Under ice cooling innitrogen atmosphere, 50 ml of n-butyl lithium/hexane solution (1.6N) wasdropwise added to the suspension. After stirring at room temperature foran hour, 15.0 g of Compound a obtained in Reference Example 1 was addedthereto followed by stirring at room temperature for 12 hours. After 50ml of water was added to the reaction mixture, the mixture was extractedwith 1 l of ethyl acetate. After washing thrice with saturated sodiumchloride aqueous solution and drying over anhydrous sodium sulfate, thesolvent was distilled off under reduced pressure. The obtained residuewas dissolved in 500 ml of dioxane and 200 ml of water and 1.0 g ofp-toluenesulfonic acid were added to the solution followed by heatingunder reflux for an hour. The mixture was concentrated under reducedpressure and the obtained residue was extracted with 1 l of ethylacetate. After washing successively with saturated sodium bicarbonateaqueous solution and saturated sodium chloride aqueous solution, theextract was dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure. The resulting residue wassubjected to silica gel column chromatography (eluent; toluene:ethylacetate=1:1) to give 9.8 g of methyl(E,Z)-11-(3-hydroxy)-propylidene-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate.A ratio of E/Z was approximately 3:7 by NMR.

The obtained product, 4.8 g, mainly composed of the Z-form and 10.0 g ofp-toluenesulfonic acid were stirred in 250 ml of acetic acid at 100° C.for 42 hours. After completion of the reaction, the solvent wasdistilled off under reduced pressure and 200 ml of methanol was added tothe residue followed by heating under reflux for 3 hours. The solventwas distilled off under reduced pressure and the residue was extractedwith 500 ml of ethyl acetate. After washing with saturated sodiumbicarbonate aqueous solution and drying over anhydrous sodium sulfate,the solvent was distilled off under reduced pressure. The obtainedresidue was subjected to silica gel column chromatography (eluent;hexane:ethyl acetate=1:1) to give 4.5 g of the product showing an E/Zratio of about 1:1.

NMR (CDCl₃, δ, ppm): 2.17-2.72(m, 2H), 3.37-3.76(m, 2H), 3.77(s, 3H),4.68-5.43(m, 1H), 5.70(t, J=7.4 Hz, 1.5H; Z form), 6.40(t, J=6.9 Hz,1.5H; E form), 6.52-8.12(m, 7H)

The aforesaid product, 3.5 g, showing an E/Z ratio of about 1:1 wasdissolved in 50 ml of pyridine and 1.7 ml of methanesulfonyl chloridewas dropwise added under ice cooling. After stirring for an hour underice cooling, the solvent was distilled off under reduced pressure. Theresidue was extracted with 200 ml of ethyl acetate. The extract waswashed in succession with 1N hydrochloric acid aqueous solution,saturated sodium bicarbonate aqueous solution and saturated sodiumchloride aqueous solution. After drying over anhydrous magnesiumsulfate, the solvent was distilled off under reduced pressure to give4.3 g of the objective compound as colorless oil.

NMR (CDCl₃, δ, ppm): --SO₂ CH₃ ; 2.93(s, 1.5H; E form), 3.00(s, 1.5H; Zform)

This product was provided for use in the following reaction step withoutparticular purification. A ratio of E/Z was about 1:1.

REFERENCE EXAMPLE 21 Methyl11-[2-(1-homopiperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound u)

The objective compound was obtained as colorless oil in a manner similarto Reference Example 11, using Compound j obtained in Reference Example10 and homopiperazine.

NMR (CDCl₃, δ, ppm): 1.4-2.0(m, 2H), 2.4-3.1(m, 12H), 3.85(s, 3H),5.02(s, 1H), 4.87 and 6.44(ABq, J=12.9 Hz, 2H), 6.75-8.05(m, 7H)

IR (neat, cm⁻¹): 2928, 1716, 1610, 1249, 1118, 1007

EXAMPLE 1 Methyl11-[2-(4-phenyl-1-piperazinyl)ethyl]thio-6,11dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 1a)

After 6.1 g of Compound j obtained in Reference Example 10 and 6.0 ml of1-phenylpiperazine were heated under reflux in 300 ml of ethanol for 7.5hours, the solvent was distilled off under reduced pressure. The residuewas extracted with 500 ml of ethyl acetate. The extract was washed insuccession with saturated sodium bicarbonate aqueous solution andsaturated sodium chloride aqueous solution and dried over anhydroussodium sulfate. Thereafter, the solvent was distilled off under reducedpressure. The obtained residue was subjected to silica gel columnchromatography (eluent; hexane:ethyl acetate:triethylamine=30:10:3). Theresulting crude product was solidified with diethyl ether to give 3.1 gof the objective compound.

EXAMPLE 2 Methyl11-[2-(4-phenyl-1-piperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate.dihydrochloride(Compound 1a')

Compound 1a, 1.2 g, obtained in Example 1 was dissolved in 200 ml ofisopropanol and 2 ml of 6N hydrochloric acid/isopropanol solution wasadded to the solution followed by stirring at room temperature for 2hours. The solvent was distilled off under reduced pressure. Theobtained crude product was recrystallized from isopropanol to give 0.9 gof the objective compound.

In Examples 3 through 7 below, the objective compound was prepared usingCompound j obtained in Reference Example 10 and the correspondingpiperazine compound in a manner similar to Example 1.

EXAMPLE 3

Methyl11-[2-[4-(4-fluorophenyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 8a)

EXAMPLE 4

Methyl11-[2-[4-(2-methoxyphenyl-1-piperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 9a)

EXAMPLE 5

Methyl11-[2-(4-benzyl-1-piperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 11a)

EXAMPLE 6

Methyl11-[2-(4-piperonyl-1-piperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 15a)

EXAMPLE 7

Methyl11-[2-[4-(diphenylmethyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 16a)

In Examples 8 through 14 below, the objective compound was preparedusing Compound j obtained in Reference Example 10 and the correspondingpiperidine compound in a manner similar to Example 1.

EXAMPLE 8

Methyl11-[2-(4-phenyl-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 37a)

EXAMPLE 9

Methyl11-[2-(4-benzyl-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 38a)

EXAMPLE 10

Methyl11-[2-[4-[2(3H)-benzimidazolon-1-yl]piperidino]-ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 47a)

EXAMPLE 11

Methyl11-[2-(4-phenyl-4-hydroxy-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 50a)

EXAMPLE 12

Methyl11-[2-(4-benzyl-4-hydroxy-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 51a)

EXAMPLE 13

Methyl11-[2-[4-(4-chlorobenzoyl)-1-piperidinyl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 53a)

EXAMPLE 14

Methyl11-[2-(1-phenyl-1,3,8-triazaspiro[4.5]decan-4-on-8-yl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 58a)

In Examples 15 through 17 below, the objective compound was preparedusing the corresponding starting material n, p or r and4-benzylpiperidine in a manner similar to Example 1.

EXAMPLE 15

Methyl2-methyl-2-[11-[2-(4-benzyl-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-yl]propionate(Compound 41a)

EXAMPLE 16

Methyl5-[2-(4-benzyl-1-piperidinyl)ethyl]thio-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-3-carboxylate(Compound 101a)

EXAMPLE 17

Methyl 5-[2-(4-benzyl-1-piperidinyl)ethyl]thio-5H-dibenzo[a,d]cyclohepten-3-carboxylate (Compound 103a)

EXAMPLE 18

Methyl(E,Z)-11-[3-(4-benzyl-1-piperazinyl)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E/Z-85a)

The objective compound was prepared using Compound t obtained inReference Example 20 and 4-benzylpiperidine in a manner similar toExample 1. A ratio of E/Z was 1:1.

In Examples 19 through 22 below, the objective compound was preparedusing the corresponding starting material c or e and the correspondingpiperazine or piperidine compound in a manner similar to Example 1.

EXAMPLE 19

Methyl(E)-11-[2-[4-(4-fluorophenyl-1-piperazinyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-73a)

EXAMPLE 20

Methyl(E,Z)-11-[2-[4-(2-pyrimidyl)-1-piperazinyl]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E/Z-76a)

EXAMPLE 21

Methyl(E)-11-[2-(4-benzyl-1-piperidinyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetate(Compound E-96a)

EXAMPLE 22

Methyl(E)-11-[2-[4-[2(3H)-benzimidazolon-1-yl]piperidino]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetate(Compound E-98a)

Physicochemical properties of compounds obtained in Examples 1 through22 are shown in Table 7-1. In Tables 7-1 to 7-5, symbol * in solvent forrecrystallization means solidification by tritylation.

                                      TABLE 7-1                                   __________________________________________________________________________                 MP (°C.)                                                  Example      [Solvent                                                         No.          for re-                               Elemental analysis                                                            (%)                        (Compound                                                                            Appear-                                                                             crystal-                                                                            NMR                IR      MS   Upper column: found        No.)   ance  lization]                                                                           (solvent) δ, ppm                                                                           (method) cm.sup.-1                                                                    m/z  Lower column:              __________________________________________________________________________                                                       calcd.                     1      white 129-130                                                                             (CDCl.sub.3) 2.30-3.34(m, 12H), 3.82                                                             (KBr tablet)                                                                          474(M+)                                                                            C.sub.28 H.sub.30                                                             N.sub.2 O.sub.3 S          (1 a)  crystal                                                                             [isopro-                                                                            (s, 1H), 5.03(s, 1H), 4.83 & 6.39                                                                3450, 2948,  C   H   N                               panol]                                                                              (ABq, J=13.1Hz, 2H), 6.30-8.06                                                                   2826, 1711,  71.11                                                                             6.23                                                                              5.80                                  (m, 12H)           1610, 1598,  70.86                                                                             6.37                                                                              5.90                                                     1242                                    2      white 188   --                 (KBr tablet)                                                                          --   C.sub.28 H.sub.32                                                             Cl.sub.2 N.sub.2                                                              O.sub.3 S                  (1a')  crystal                                                                             (dec.)                   1714, 1599,  C   H   N                               [isopro-                 1494, 1118,  61.75                                                                             6.21                                                                              5.15                            panol]                   1006         61.42                                                                             5.89                                                                              5.12               3      yellow                                                                              --    (CDCl.sub.3) 2.4-3.3(m, 12H), 3.81                                                               (CHCl.sub.3)                                                                          492(M+)                                                                            --                         (8 a)  amorphous   (s,3H), 3.83(s,3H), 4.86 & 6.41                                                                  2824, 1713,                                                (ABq, J=11.7Hz, 2H), 5.03(s, 1H),                                                                1611, 1508,                                                6.7-7.4(m, 8H), 7.67(dd, J=2.5,                                                                  1294, 1132,                                                8.5Hz, 1H), 7.88(d, J=2.5Hz, 1H)                                                                 1120, 1005                              4      colorless                                                                           --    (CDCl.sub.3) 2.4-3.3(m, 12H), 3.81                                                               (CHCl.sub.3)                                                                          504(M+)                                                                            --                         (9 a)  oil         (s, 3H), 3.83(s, 3H), 4.85 & 6.44                                                                2936, 2806,                                                (ABq, J=12.8Hz, 2H), 5.07(s, 1H),                                                                1708, 1610,                                                6.7-7.4(m, 9H), 7.76(dd, J=2.3,                                                                  1496, 1005                                                 8.5Hz, 1H), 7.98(d, J=2.3Hz, 1H)                           5      colorless                                                                           --    (CDCl.sub.3) 2.05-2.65(m, 12H), 3.46                                                             (CHCl.sub.3)                                                                          487(M+)                                                                            --                         (11a)  oil         (s, 2H), 3.83(s, 3H), 4.86 & 6.45                                                                2816, 1714,                                                (ABq, J=12.0Hz, 2H), 5.06(s, 1H),                                                                1611, 1120,                                                6.98-7.44(m,9H), 7.78(dd, J=2.2,                                                                 1006                                                       8.6Hz, 1H), 7.98(d, J=2.2Hz, 1H)                           6      colorless                                                                           --    (CDCl.sub.3) 2.25-2.75(m, 12H), 3.36                                                             (CHCl.sub.3)                                                                          532(M+)                                                                            --                         (15a)  oil         (s, 2H), 3.81(s, 3H), 4.82 & 6.40                                                                1702, 1602,                                                (ABq, J=12.2Hz, 2H), 5.03(s, 1H),                                                                1296, 1121,                                                5.85(s, 2H), 6.55-6.8(m, 3H),                                                                    1004                                                       6.82(d, J=4.6Hz, 1H), 7.1-7.35                                                (m, 4H), 7.72(dd, J=2.5, 8.5Hz,                                               1H), 7.93(d, J=2.5Hz, 1H)                                  7      colorless                                                                           --    (CDCl.sub.3) 3.84(s, 3H), 4.20(s,                                                                (CHCl.sub.3)                                                                          564(M+)                                                                            --                         (16a)  oil         1H), 4.87 & 6.43(ABq, J=12.7Hz,                                                                  1715, 1610,                                                2H), 5.07(s, 1H), 6.84(d, J=8.6                                                                  1495, 1241,                                                Hz, 1H), 7.78(dd, J=2.2, 8.6Hz,                                                                  1117, 1005,                                                1H), 7.97(d, J=2.2Hz, 1H)                                  8      colorless                                                                           --    (CDCl.sub.3) 1.5-3.2(m, 13H), 3.84                                                               (CHCl.sub.3)                                                                          473(M+)                                                                            --                         (37a)  oil         (s, 3H), 4.95 & 6.50(ABq, J=12.7                                                                 1719, 1609,                                                Hz, 2H), 5.14(s, 1H), 6.87(d,                                                                    1496, 1247,                                                J=8.5Hz, 1H), 7.05-7.45(m, 9H),                                                                  1128, 1009                                                 7.81(dd, J=2.2, 8.5Hz, 1H), 8.03                                              (d, J=2.2Hz, 1H)                                           9      colorless                                                                           --    (CDCl.sub.3) 1.0-2.2(m, 7H), 2.2-3.2                                                             (CHCl.sub.3)                                                                          487(M+)                                                                            --                         (38a)  oil         (m, 8H), 3.83(s, 3H), 4.85 & 6.41                                                                2924, 1713,                                                (ABq, J=13.9Hz, 2H), 5.06(s, 1H),                                                                1611, 1295,                                                6.8-7.4(m, 10H), 7.75(dd, J=2.0,                                                                 1120, 1007                                                 8.5Hz, 1H), 7.95(d, J=2.0Hz, 1H)                           10     colorless                                                                           --    (DMSO-d.sub.6) 1.5-3.0(m, 12H), 3.82                                                             (CHCl.sub.3)                                                                          529(M+)                                                                            --                         (47a)  oil         (s, 3H), 4.12(m, 1H), 5.08 & 6.31                                                                1718, 1686,                                                (ABq, J=12.7Hz, 2H), 5.51(s, 1H),                                                                1251, 1119,                                                6.91(d, J=8.6Hz, 1H), 6.95-7.5                                                                   1015                                                       (m, 8H), 7.75(dd, J=2.2, 8.6Hz,                                               1H), 8.04(d, J=2.2Hz, 1H)                                  11     colorless                                                                           --    (CDCL.sub.3) 3.87(s, 3H), 4.90 & 6.45                                                            (CHCL.sub.)                             (50a)  oil         (ABq, J=12.9Hz, 2H), 5.09(s,, 1H), 1715, 1610,                                6.86(d, J=8.6Hz, 1H), 7.79(dd,                                                                   1247, 1117,                                                J=2.2, 8.6Hz, 1H), 8.00(d, J=                                                                    1005                                                       2.2Hz, 1H)                                                 12     colorless                                                                           --    (CDCl.sub.3) 1.2-2.7(m, 12H), 2.73                                                               (neat)  503(M+)                                                                            --                         (51a)  oil         (s, 2H), 3.86(s, 3H), 4.88 & 6.44                                                                2916, 1696,                                                (ABq, J=12.7Hz, 2H), 5.06(s, 1H),                                                                1609, 1570,                                                6.84(d, J=8.6Hz, 1H), 7.00-7.40                                                                  1491, 1113,                                                (m, 9H), 7.78(dd, J=2.2, 8.6Hz,                                                                  1008                                                       1H), 7.98(d, J=2.2Hz, 1H)                                  13     colorless                                                                           --    (CDCl.sub.3) 1.80-3.50(m, 13H), 3.87                                                             (CHCl.sub.3)                                                                          536(M+)                                                                            --                         (53a)  oil         (s, 3H), 4.90 & 6.43(ABq, J=12.7                                                                 2954, 2930,                                                Hz, 2H), 5.09(s, 1H), 6.86(d, J=                                                                 1715, 1293,                                                8.6Hz, 1H), 7.20-7.35(m, 4H),                                                                    1132, 1121                                                 7.43(d, J=8.6Hz, 2H), 7.85(d,                                                 J=8.6Hz, 2H), 7.70-7.95(m, 2H)                             14     colorless                                                                           --    (CDCl.sub.3) 1.6-1.8(m, 2H), 2.4-3.0                                                             (CHCl.sub.3)                                                                          543(M+)                                                                            --                         (58a)  oil         (m, 10H), 3.86(s, 3H), 4.72(s,                                                                   2926, 1703,                                                2H), 4.90 & 6.46(ABq, J=12.8Hz,                                                                  1600, 1499,                                                2H), 5.13(s, 1H), 6.6-7.4(m,                                                                     1376, 1243,                                                10H), 7.75(dd, J=2.0, 8.5H, 1H),                                                                 1118, 1006                                                 8.00(d, J=2.0Hz, 1H)                                       15     colorless                                                                           --    (CDCl.sub.3) 1.1-2.9(m, 15H), 1.55(s,                                                            (CHCl.sub.3)                                                                          529(M+)                                                                            --                         (41a)  oil         6H), 3.61(s, 3H), 4.99(s, 1H),                                                                   2922, 1726,                                                4.80 & 6.29(ABq, J=13.0Hz, 2H),                                                                  1496, 1265,                                                6.7-7.35(m, 12H)   1147, 1124,                                                                   1105, 1013,                                                                   906                                     16     pale  --    (CDCl.sub.3) 1.13-1.99(m, 9H), 2.35                                                              (CHCl.sub.3)                                                                          485(M+)                                                                            --                         (101a) yellow      -2.99(m, 8H), 3.62-3.96(m, 2H),                                                                  1717, 1301,                                    oil         3.83(s, 3H), 5.16(s, 1H), 6.95                                                                   1280, 1105                                                 -7.30(m, 10H), 7.80(dd, J=1.5,                                                7.9Hz, 1H), 7.92(s, 1H)                                    17     pale  --    (CDCl.sub.3) 1.11-2.03(m, 9H), 2.35                                                              (CHCl.sub.3)                                                                          483(M+)                                                                            --                         (103a) yellow      (s, 2H), 2.38-2.81(m, 4H), 3.90                                                                  1716, 1299,                                    oil         (s, 3H), 5.29(s, 1H), 7.01(s,                                                                    1279, 1110                                                 1H), 7.02(s, 1H), 7.06-7.42(m,                                                10H), 7.92(dd, J=1.1, 9.7Hz, 1H),                                             7.99(s, 1H)                                                18     colorless                                                                           --    (CDCl.sub.3) 0.8-2.0(m, 7H), 2.1-2.9                                                             (neat)  467(M+)                                                                            --                         (E/Z-85a)                                                                            oil         (m, 8H), 3.78(s, 3H), 5.18(bs,                                                                   2916, 1718,                                                2H), 5.65(t, J=7.0Hz; Z form),                                                                   1604, 1118,                                                5.99(t, J=7.0Hz; E form), 6.6-                                                                   1004                                                       8.0(m, 12H), 7.93(d, J=2.4Hz, 1H)                          19     colorless                                                                           --    (CDCl.sub.3) 2.3-3.4(m, 10H), 3.83                                                               (KBr tablet)                                                                          458(M+)                                                                            --                         (E-73a)                                                                              amorphous   (s, 3H), 4.7-5.6(m, 2H), 6.25(t,                                                                 1707, 1605,                                                J=5.5Hz, 1H), 6.6-7.5(m, 9H),                                                                    1504, 1240,                                                7.73(dd, J=2.2, 8.6Hz, 1H), 8.00                                                                 1002                                                       (d, J=2.2Hz, 1H)                                           20     colorless                                                                           --    (CDCl.sub.3) 2.35-2.7(m, 4H), 3.0-                                                               (KBr tablet)                                                                          442(M+)                                                                            --                         (E/Z-76a)                                                                            oil         3.35(m, 2H), 3.88(s, 3H), 3.65-                                                                  1713, 1585,                                                4.0(m, 4H), 4.6-5.6(m, 2H), 6.30                                                                 1357, 1244,                                                (t, J=6.8Hz; Z form), 6.45(t, J=                                                                 1002                                                       4.8Hz; E form), 6.79(d, J=8.6Hz,                                              1H), 7.0-7.5(m, 5H), 7.78(dd, J=                                              2.2, 8.6Hz, 1H), 8.05(d, J=2.2Hz,                                             1H), 8.27(d, J=4.6Hz, 2H)                                  21     colorless                                                                           --    (CDCl.sub.3) 1.0-3.2(m, 11H), 3.47                                                               (neat)  467(M+)                                                                            --                         (E-96a)                                                                              oil         (s, 2H), 3.61(s, 3H), 4.85-5.3                                                                   2918, 1735,                                                (m, 2H), 6.14(t, J=6.8Hz, 1H),                                                                   1489, 1011                                                 6.66(d, J=9Hz, 1H), 6.8-7.34(m,                                               11H)                                                       22     colorless                                                                           --    (CDCl.sub.3) 1.35-3.35(m, 11H), 3.54                                                             (CHCl.sub.3)                                                                          509(M+)                                                                            --                         (E-98a)                                                                              oil         (s, 2H), 3.68(s, 3H), 4.65-5.5                                                                   1689, 1486,                                                (m, 2H), 6.22(t, J=6.6Hz, 1H),                                                                   1148, 1008                                                 6.73(d, J=8.4Hz, 1H), 6.8-7.5                                                 (m, 10H)                                                   __________________________________________________________________________

EXAMPLE 2311-[2-(4-Phenyl-1-piperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid.monohydrate (Compound 1b')

Compound 1a, 0.8 g, obtained in Example 1 was dissolved in a solventmixture of 300 ml of methanol and 10 ml of water and, 80 mg of sodiumhydroxide was added to the solution followed by heating under reflux for4 hours. After allowing to cool, 4N hydrochloric acid aqueous solutionwas added to the mixture to adjust pH to 7. The mixture was concentratedunder reduced pressure. Precipitated crystals were taken by filtration.After washing with water, 0.7 g of the objective compound was obtainedas white solid.

In Examples 24 through 30 below, the objective compound was prepared byhydrolyzing esters of the corresponding oxepine derivatives in a mannersimilar to EXAMPLE 23.

EXAMPLE 24

11-[2-[4-(4-Fluorophenyl-1-piperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound 8b)

EXAMPLE 2511-[2-[4-(2-Methoxyphenyl-1-piperazinyl)ethyl]thio-6,11dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound 9b) EXAMPLE 26

11-[2-(4-Benzyl-1-piperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid.monohydrate (Compound 11b')

EXAMPLE 27

11-[2-(4-Piperonyl-1-piperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound 15b)

EXAMPLE 28

11-[2-[4-(Diphenylmethyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound 16b)

EXAMPLE 29

11-[2-(4-Phenyl-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid.0.5 hydrate (Compound 37b')

EXAMPLE 30

11-[2-(4-Benzyl-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound 38b)

EXAMPLE 31 Sodium11-[2-(4-Benzyl-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 38b')

Compound 38b, 45 g, obtained in Example 30 was suspended in 500 ml ofmethanol and 5.3 g of sodium methoxide was added to the suspensionfollowed by stirring at room temperature for 4 hours. The solvent wasdistilled off under reduced pressure. The resulting crude product wassolidified with hexane to give 47 g of the objective compound.

EXAMPLE 3211-[2-[4-[2(3H)-Benzimidazolon-1-yl]piperidino]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid.0.5 isopropanol.0.5 hydrate (Compound 47b')

The objective compound was prepared by hydrolyzing Compound 47a obtainedin Example 10 in a manner similar to Example 23.

EXAMPLE 33 Sodium11-[2-[4-[2(3H)-Benzimidazolon-1-yl]piperidino]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate.2.5hydrate (Compound 47b")

Compound 47b' obtained in Example 32 was converted into the sodium saltin a manner similar to Example 31.

In Examples 34 through 38 below, the objective compound was prepared byhydrolyzing esters of the corresponding oxepine derivatives in a mannersimilar to Example 23.

EXAMPLE 34

11-[2-(4-Phenyl-4-hydroxy-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid.0.75 hydrate (Compound 50b')

EXAMPLE 35

11-[2-(4-Benzyl-4-hydroxy-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid.0.2 isopropanol (Compound 51b')

EXAMPLE 36

11-[2-[4-(4-Chlorobenzoyl-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid.0.1 isopropanol. 0.5 hydrate (Compound 53b')

EXAMPLE 37

11-[2-(1-Phenyl-1,3,8-triazaspiro[4.5]decan-4-on-8-yl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid.25 0.25 hydrate (Compound 58b')

EXAMPLE 38

2-Methyl-2-[11-[2-(4-benzyl-1-piperidinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-yl]propionate(Compound 41)

EXAMPLE 395-[2-(4-Benzyl-1-piperidinyl)ethyl]thio-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-3-carboxylicacid.0.5 fumarate (Compound 101b')

Compound 101a, 0.33 g, obtained in Example 16 was hydrolyzed in a mannersimilar to Example 23 to give 0.3 g of the corresponding Compound 101b.This compound was dissolved in 50 ml of acetone and 80 mg of fumaricacid was added to the solution followed by stirring at room temperaturefor 2 hours. The solvent was distilled off under reduced pressure. Theresulting crude product was recrystallized from isopropanol to prepare0.14 g of the objective compound.

EXAMPLE 405-[2-(4-Benzyl-1-piperidinyl)ethyl]thio-5H-dibenzo[a,d]cyclohepten-3-carboxylicacid.0.5 fumarate.0.5 isopropanol (Compound 103b')

The objective compound was prepared using Compound 103a obtained inExample 17 in a manner similar to Example 39.

EXAMPLE 41(E,Z)-11-[3-(4-Benzyl-1-piperazinyl)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid.1.5 hydrate (Compound 85b')

The objective compound was prepared by hydrolyzing Compound E/Z-85aobtained in Example 18 in a manner similar to Example 23.

A ratio of E/Z was 38:62.

In Examples 42 and 43 below, the objective compound was prepared byhydrolyzing esters of the corresponding oxepine derivatives in a mannersimilar to Example 23.

EXAMPLE 42

(E)-11-[2-[4-(4-Fluorophenyl)-1-piperazinyl]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid.isopropanol.monohydrate (Compound E-73b')

EXAMPLE 43(E,Z)-11-[2-[4-(2-Pyrimidyl)-1-piperazinyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound E/Z-76b)

A ratio of E/Z was 85:15.

EXAMPLE 44(E)-11-[2-(4-Benzyl-1-piperidinyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-aceticacid.0.5 fumarate (Compound E-96b')

Compound E-96a, 2.0 g, obtained in Example 21 was hydrolyzed in a mannersimilar to Example 23 to give 1.7 g of the corresponding Compound E-96b.This compound was dissolved in 200 ml of acetone and 0.43 g of fumaricacid was added to the solution followed by stirring at room temperaturefor an hour. The precipitated crystals were taken by filtration to give1.5 g of the objective compound.

EXAMPLE 45(E)-11-[2-[4-[2(3H)-Benzimidazolon-1-yl]piperidino]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-aceticacid.monohydrate (Compound E-98b')

The objective compound was prepared by hydrolyzing Compound E-98aobtained in Example 22 in a manner similar to Example 23.

EXAMPLE 46 Sodium(E)-11-[2-[4-[2(3H)-benzimidazolon-1-yl]piperidino]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetate(Compound E-98b")

Compound E-98b' obtained in Example 45 was converted into the sodiumsalt in a manner similar to Example 31.

Physicochemical properties of the compounds obtained in Examples 23through 46 are shown in Table 7-2.

                                      TABLE 7-2                                   __________________________________________________________________________                MP (°C.)                                                   Example     [Solvent                                                          No.         for re-                               Elemental analysis (%)      (Compound                                                                           Appear-                                                                             crystal-                                                                            NMR               IR      MS    Upper column: found         No.)  ance  lization]                                                                           (solvent) δ, ppm                                                                          (method) cm.sup.-1                                                                    m/z   Lower column:               __________________________________________________________________________                                                      calcd.                      23    white 215   (DMSO-d.sub.6) 2.50-3.83(m, 12H),                                                               (KBr tablet)                                                                          460 (M+)                                                                            C.sub.27 H.sub.28                                                             N.sub.2 O.sub.3                                                               S.H.sub.2)                  (1b') crystal                                                                             (dec.)                                                                              5.08 & 6.23(ABq, J = 12.5Hz, 2H),                                                               3400, 2936,   C  H  N                                 [isopro-                                                                            5.51(s, 1H), 6.79-8.04(m, 12H)                                                                  2824, 1694,   67.39                                                                            6.06                                                                             5.59                              panol]                  1599, 1232    67.76                                                                            6.32                                                                             5.85                  24    white 165-166                                                                             (DMSO-d.sub.6) 2.3-2.8(m, 8H), 3.0-                                                             (KBr tablet)                                                                          478 (M+)                                                                            C.sub.27 H.sub.27                                                             FN.sub.2 O.sub.3 S          (8 b) amorphous                                                                           (dec.)                                                                              3.1(m, 4H), 5.05 & 6.28(ABq, J =                                                                3400, 1607,   C  H  N                                 [isopro-                                                                            12.6Hz, 2H), 5.45(s, 1H), 6.85-                                                                 1509, 1384,   67.55                                                                            5.65                                                                             5.58                              panol]*                                                                             7.1(m, 5H), 7.4-7.5(m, 4H), 7.71                                                                1232          67.76                                                                            5.69                                                                             5.85                                    (dd, J = 2.2, 8.7Hz, 1H), 7.99(d,                                             J = 2.2Hz, 1H)                                              25    white 171-175                                                                             (DMSO-d.sub.6) 3.0-3.7(m, 12H), 3.81                                                            (KBr tablet)                                                                          490 (M+)                                                                            C.sub.28 H.sub.30                                                             N.sub.2 O.sub.4 S           (9 b) amorphous                                                                           [isopro-                                                                            (s, 3H), 5.10 & 6.16(ABq, J = 12.9                                                              1694, 1609,   C  H  N                                 panol]*                                                                             Hz, 2H), 5.54(s, 1H), 6.90(d,                                                                   1499, 1455,   68.23                                                                            6.35                                                                             5.88                                    J = 8.5Hz, 1H), 6.9-7.1(m, 4H),                                                                 1200, 1115,   68.55                                                                            6.16                                                                             5.71                                    7.4-7.65(m, 4H), 7.74(dd, J = 2.2,                                                              1013                                                        8.5Hz, 1H), 8.06(d, J = 2.2Hz, 1H)                          26    white 112-115                                                                             (DMSO-d.sub.6) 2.2-2.7(m, 12H), 3.42                                                            (KBr tablet)                                                                          474 (M+)                                                                            C.sub.28 H.sub.30                                                             N.sub.2 O.sub.3                                                               S.H.sub.2 O                 (11b')                                                                              crystal                                                                             (dec.)                                                                              (s, 2H), 5.01 & 6.24(ABq, J = 12.7                                                              3400, 1609,   C  H  N                                 [iso- Hz, 2H), 5.39(s, 1H), 6.81(d, J =                                                               1384, 1232,   68.33                                                                            6.25                                                                             5.54                              propyl                                                                              8.6Hz, 1H), 7.2-7.5(m, 9H), 7.69                                                                1008          68.27                                                                            6.55                                                                             5.69                              ether]                                                                              (dd, J = 2.2, 8.6Hz, 1H), 7.95(d,                                             2.2Hz, 1H)                                                  27    white 218-220                                                                             (DMSO-d.sub.6) 2.2-2.7(m, 12H), 3.34                                                            (KBr tablet)                                                                          518 (M+)                                                                            C.sub.29 H.sub.30                                                             N.sub.2 O.sub.5 S           (15b) crystal                                                                             (dec.)                                                                              (s, 2H), 5.04 & 6.26(ABq, J = 12.7                                                              1670, 1609,   C  H  N                                 [isopro-                                                                            Hz, 2H), 5.43(s, 1H), 5.98(s,                                                                   1491, 1242,   67.09                                                                            5.95                                                                             5.24                              panol]                                                                              2H), 6.72(d, J = 7.9Hz, 1H), 6.8-                                                               1040          67.16                                                                            5.83                                                                             5.40                                    6.85(m, 2H), 6.86(d, J = 8.6Hz,                                               1H), 7.35-7.5(m, 4H), 7.71(dd,                                                J = 2.2, 8.6Hz, 1H), 7.98(d, J =                                              2.2Hz, 1H)                                                  28    white 145-148                                                                             (DMSO-d.sub.6) 2.2-2.7(m, 12H), 4.26                                                            (KBr tablet)                                                                          550 (M+)                                                                            C.sub.34 H.sub.34                                                             N.sub.2 O.sub.3 S           (16b) crystal                                                                             [isopro-                                                                            (s, 1H), 5.04 & 6.23(ABq, J = 12.6                                                              1683, 1608,   C  H  N                                 panol]                                                                              Hz, 2H), 5.44(s, 1H), 6.86(d,                                                                   1493, 1451,   73.98                                                                            6.35                                                                             5.00                                    J = 8.6Hz, 1H), 7.70(dd, J = 2.2,                                                               1232, 1006    74.15                                                                            6.22                                                                             5.09                                    8.6Hz, 1H), 7.98(d, J = 2.2Hz, 1H)                          29    white 182-184                                                                             (DMSO-d.sub.6) 1.65-3.0(m, 13H), 5.06                                                           (KBr tablet)                                                                          459 (M+)                                                                            C.sub.28 H.sub.29                                                             NO.sub.3 S.0.5H.sub.2                                                         O                           (37b')                                                                              crystal                                                                             [isopro-                                                                            & 6.27(ABq, J = 12.7Hz, 2H), 5.48                                                               1680, 1605,   C  H  N                                 panol]                                                                              (s, 1H), 6.88(d, J = 8.5Hz, 1H),                                                                1494, 1318,   71.85                                                                            6.23                                                                             2.98                                    7.15-7.5(m, 9H), 7.72(dd, J = 2.2,                                                              1233, 1104,   71.77                                                                            6.45                                                                             2.99                                    8.5Hz, 1H), 8.01(d, J = 2.2Hz, 1H)                                                              1007                                      30    white 205-206                                                                             (DMSO-d.sub.6) 1.0-1.9(m, 7H), 2.2-                                                             (KBr tablet)                                                                          473 (M+)                                                                            C.sub.29 H.sub.31                                                             NO.sub.3 S                  (38b) crystal                                                                             [isopro-                                                                            2.85(m, 8H), 5.03 & 6.25(ABq, J =                                                               2912, 1687,   C  H  N                                 panol]                                                                              12.6Hz, 2H), 5.42(s, 1H), 6.86                                                                  1608, 1494,   73.48                                                                            6.72                                                                             2.92                                    (d, J = 8.6Hz, 1H), 7.1-7.5(m, 9H),                                                             1449, 1323,   73.54                                                                            6.60                                                                             2.96                                    7.70(dd, J = 2.2, 8.6Hz, 1H), 7.97                                                              1229, 1019                                                  (d, J = 2.2Hz, 1H)                                          31    white 119-121                                                                               --              (KBr tablet)                                                                          --    C.sub.29 H.sub. 30                                                            NO.sub.3 SNa.0.5H.sub.2                                                       O                           (38b')                                                                              solid [hexane]*               2918, 1612,   C  H  N                                                         1582, 1548,   68.80                                                                            6.44                                                                             2.93                                                      1385, 1252,   69.03                                                                            6.19                                                                             2.78                                                      1227, 1105,                                                                   1011                                      32    white 185-188                                                                             (DMSO-d.sub.6) 1.55-3.1(m, 12H),                                                                (KBr tablet)                                                                          515 (M+)                                                                            C.sub.29 H.sub.29                                                             N.sub.3 O.sub.4                                                               S.0.5C.sub.3 H.sub.8                                                          O.                          (47b')                                                                              crystal                                                                             [aceto-                                                                             4.14(m, 1H), 5.07 & 6.28(ABq, J =                                                               1695, 1485,   0.5C.sub.2 H.sub.3 N                    nitrile/                                                                            12.7Hz, 2H), 5.48(s, 1H), 6.89                                                                  1386          C  H  N                                 isopro-                                                                             (d, J = 8.6Hz, 1H), 6.95-7.5(m, 66.41                                                                            5.90                                                                             8.45                              panol]                                                                              8H), 7.72(dd, J = 2.2, 8.6Hz, 1H),                                                                            66.75                                                                            6.22                                                                             8.57                                    8.06(d, J = 2.2Hz, 1H), 10.83(s,                                              1H)                                                         33    white 224- 227                                                                              --              (KBr tablet)                                                                          --    C.sub.29 H.sub.28                                                             N.sub.3 O.sub.4                                                               SNa.2.5H.sub.2 O            (47b")                                                                              crystal                                                                             [methanol]              1683, 1583,   C  H  N                                                         1543, 1485,   59.77                                                                            5.72                                                                             7.10                                                      1379, 1256,   59.78                                                                            5.71                                                                             7.21                                                      1229, 1109,                                                                   1006                                      34    white 150-154                                                                             (DMSO-d.sub.6) 1.5-1.6(m, 2H), 1.8-                                                             (KBr tablet)                                                                          475 (M+)                                                                            C.sub.28 H.sub.29                                                             NO.sub.4 S.0.75H.sub.2                                                        O                           (50b')                                                                              crystal                                                                             [isopro-                                                                            2.0(m, 2H), 2.35-2.75(m, 8H),                                                                   1611, 1584,   C  H  N                                 panol]                                                                              5.05 & 6.28(ABq, J = 12.7Hz, 2H),                                                               1550, 1375,   68.60                                                                            6.41                                                                             2.88                                    6.87(d, J = 8.5Hz, 1H), 7.15-7.5                                                                1228, 1006    68.76                                                                            6.29                                                                             2.86                                    (m, 9H), 7.71(dd, J = 2.1, 8.5Hz,                                             1H), 8.01(d, J = 2.1Hz, 1H)                                 35    white 232   (DMSO-d.sub.6) 1.25-1.5(m, 4H), 2.2-                                                            (KBr tablet)                                                                          489 (M+)                                                                            C.sub.29 H.sub.31                                                             NO.sub.4 S.0.2C.sub.3                                                         H.sub.8 O                   (51b')                                                                              crystal                                                                             [isopro-                                                                            2.75(m, 8H), 2.63(s, 2H), 5.02 &                                                                1608, 1492,   C  H  N                                 panol]                                                                              6.25(ABq, J = 12.6Hz, 2H), 5.41(s,                                                              1383, 1232,   70.98                                                                            6.43                                                                             2.49                                    1H), 6.85(d, J = 8.6Hz, 1H), 7.15-                                                              1107, 1009    70.87                                                                            6.55                                                                             2.79                                    7.45(m, 9H), 7.70(dd, J = 2.2, 8.6                                            Hz, 1H), 7.96(d, J = 2.2Hz, 1H)                             36    pale  138-139                                                                             (DMSO-d.sub.6) 1.4-3.5(m, 13H), 5.05                                                            (KBr tablet)                                                                          522 (M+)                                                                            C.sub.29 H.sub.28                                                             ClNO.sub.4 S.0.1            (53b')                                                                              yellow                                                                              [iso- & 6.27(ABq, J = 12.6Hz, 2H), 5.46                                                               1676, 1608,   C.sub.6 H.sub.14                                                              O.0.5H.sub.2 O                    solid propyl                                                                              (s, 1H), 6.87(d, J = 8.6Hz, 1H),                                                                1587, 1376,   C   H N                                 ether]*                                                                             7.35-7.5(m, 4H), 7.59(d, J = 8.6Hz,                                                             1229, 1091,   65.81                                                                            5.39                                                                             2.22                                    2H), 7.71(dd, J = 2.1, 8.6Hz, 1H),                                                              1009          65.46                                                                            5.68                                                                             2.58                                    7.97(d, J = 8.6Hz, 2H), 7.99(d,                                               J = 2.1Hz, 1H)                                              37    white 186-189                                                                             (DMSO-d.sub.6) 1.56(d, J = 13.6Hz, 2H),                                                         (KBr tablet)                                                                          529 (M+)                                                                            C.sub.30 H.sub.31                                                             N.sub.3 O.sub.4                                                               S.0.25H.sub.2 O             (58b')                                                                              solid [isopro-                                                                            2.4-2.9(m, 10H), 4.57(s, 2H),                                                                   1710, 1598,   C  H  N                                 panol]                                                                              5.06 & 6.26(ABq, J = 12.6Hz, 2H),                                                               1497, 1379,   67.29                                                                            5.82                                                                             7.69                                    5.54(s, 1H), 6.75-7.2(m, 5H),                                                                   1105, 1009    67.46                                                                            5.94                                                                             7.87                                    6.88(d, J = 8.5Hz, 1H), 7.72(dd,                                              J = 2.1, 8.5Hz, 1H), 8.04(d, J =                                              2.1Hz, 1H), 8.64(s, 1H)                                     38    white 84-86 (DMSO-d.sub.6) 1.1-1.3(m, 2H), 1.35-                                                            (KBr tablet)                                                                          515 (M+)                                                                            C.sub.32 H.sub.37                                                             NO.sub.3 S                  (41b) solid [water]*                                                                            1.6(m, 3H), 1.43 & 1.45(each s,                                                                 2926, 1720,   C  H  N                                       6H), 1.85-2.0(m, 2H), 2.35-2.9                                                                  1496, 1453,   74.21                                                                            7.45                                                                             2.66                                    (m, 8H), 5.33(s, 1H), 4.91 & 6.13                                                               1231, 1123,   74.53                                                                            7.23                                                                             2.72                                    (ABq, J = 12.8Hz, 2H), 6.76(d, J =                                                              1014                                                        8.4Hz, 1H), 7.1-7.45(m, 11H)                                39    pale  127-130                                                                             (CD.sub.3 OD) 1.20-1.86(m, 5H), 2.35-                                                           (KBr tablet)                                                                          469 (M+)                                                                            C.sub.30 H.sub.31                                                             NO.sub.2 S.0.5C.sub.4                                                         H.sub.4 O.sub.4             (101b')                                                                             yellow                                                                              [isopro-                                                                            3.20(m, 12H), 3.56-3.94(m, 2H),                                                                 3420, 2920,   C  H  N                           crystal                                                                             panol]                                                                              5.21(s, 1H), 7.03-7.33(m, 10H),                                                                 1695, 1585,   72.60                                                                            6.60                                                                             2.55                                    7.75-7.86(m, 2H)  1453, 1372,   72.84                                                                            6.30                                                                             2.65                                                      1244                                      40    pale  100-115                                                                             (DMSO-d.sub.6) 1.18-2.11(m, 5H), 2.26-                                                          (KBr tablet)                                                                          467 (M+)                                                                            C.sub.30 H.sub.29                                                             NO.sub.2 S.0.5C.sub.4                                                         H.sub.4 O.sub.4.            (103b')                                                                             yellow                                                                              (dec.)                                                                              2.60(m, 8H), 2.63-2.92(m, 2H),                                                                  3400, 2922,   0.5C.sub.3 H.sub.8 O              crystal                                                                             [isopro-                                                                            5.44(s, 1H), 6.99(s, 2H), 7.01-                                                                 1698, 1582,   C  H  N                                 panol]                                                                              7.49(m, 10H), 7.84(dd, J = 1.3,                                                                 1372          72.23                                                                            6.51                                                                             2.41                                    9.0Hz, 1H), 8.02(s, 1H)         72.41                                                                            6.35                                                                             2.52                  41    white 146-149                                                                             (DMSO-d.sub.6) 5.70(t, J = 6.7Hz; Z                                                             (KBr tablet)                                                                          453 (M+)                                                                            C.sub.30 H.sub.31                                                             NO.sub.3 .1.5H.sub.2 O      (E/Z-85b')                                                                          solid [water]*                                                                            form), 6.06(t, J = 7.5Hz; E form),                                                              2920, 1605,   C  H  N                                       6.80(d, J = 8.4Hz; E form), 6.88                                                                1486, 1454,   75.09                                                                            7.22                                                                             2.82                                    (d, J = 8.6Hz; Z form), 7.76(d, J =                                                             1367, 1242,   74.97                                                                            7.13                                                                             2.91                                    2.2Hz; Z form), 7.87(d, J = 2.0Hz;                                                              1004                                                        E form)                                                     42    white 236-238                                                                             (DMSO-d.sub.6) 2.4-3.7(m, 10H), 4.95-                                                           (KBr tablet)                                                                          444 (M+)                                                                            C.sub.27 H.sub.25                                                             FN.sub.2 O.sub.3.C.sub.3                                                       H.sub.8 O.                 (E-73b')                                                                            crystal                                                                             (dec.)                                                                              5.65(m, 2H), 6.17(t, J = 6.7Hz,                                                                 1608, 1509,   H.sub.2 O                               [isopro-                                                                            1H), 6.83(d, J = 8.5Hz, 1H), 6.85-                                                              1370, 1224    C  H  N                                 panol]                                                                              7.55(m, 8H), 7.72(dd, J = 2.2,  69.10                                                                            6.60                                                                             5.33                                    8.5Hz, 1H), 7.92(d, J = 2.2Hz, 1H)                                                                            68.95                                                                            6.75                                                                             5.36                  43    pale  161-165                                                                             (DMSO-d.sub.6) 2.3-3.8(m, 10H), 4.9-                                                            (KBr tablet)                                                                          428 (M+)                                                                            C.sub.25 H.sub.24                                                             N.sub.4 O.sub.3             (E/Z-76b)                                                                           yellow                                                                              [isopro-                                                                            5.65(m, 2H), 5.86(t, J = 7.1Hz; Z                                                               1584, 1551,   C  H  N                           crystal                                                                             panol]                                                                              form), 6.18(t, J = 6.6Hz; E form),                                                              1487, 1450,   69.91                                                                            5.78                                                                             13.22                                   6.6-8.4(m, 10H)   1360          70.08                                                                            5.65                                                                             13.08                 44    white 203-204.5                                                                           (DMSO-d.sub.6) 1.1-2.55(m, 9H), 2.46                                                            (KBr tablet)                                                                          453 (M+)                                                                            C.sub.30 H.sub.31                                                             NO.sub.3.0.5C.sub.4                                                           H.sub.4 O.sub.4             (E-96b')                                                                            solid [acetone]*                                                                          (d, J = 6.6Hz, 2H), 2.92(d, J = 6.6                                                             1704, 1488,   C  H  N                                       Hz, 1H), 3.48(s, 2H), 4.0-5.5(m,                                                                1357, 1249,   74.92                                                                            6.64                                                                             2.79                                    2H), 6.08(t, J = 6.6Hz, 1H), 6.57                                                               1227, 1003    75.12                                                                            6.50                                                                             2.74                                    (s, 1H), 6.67(d, J = 8.4Hz, 1H),                                              7.0-7.5(m, 11H)                                             45    white 260-262                                                                             (DMSO-d.sub.6) 1.5-3.6(m, 10H), 3.51                                                            (KBr tablet)                                                                          495 (M+)                                                                            C.sub.30 H.sub.29                                                             N.sub.3 O.sub.4.H.sub.2                                                       O                           (E-98b')                                                                            solid [isopro-                                                                            (s, 2H), 4.05-4.2(m, 1H), 4.93 &                                                                1699, 1489,   C  H  N                                 panol]*                                                                             5.40(each bs, 2H), 6.13(t, J = 6.7                                                              1386, 1003    70.31                                                                            6.45                                                                             8.35                                    Hz, 1H), 6.68(d, J = 8.5Hz, 1H),                                                                              70.16                                                                            6.08                                                                             8.18                                    6.95-7.5(m, 10H)                                            46    white 218-219.5                                                                           (DMSO-d.sub.6) 1.5-2.5(m, 4H), 2.9-                                                             (KBr tablet)                                                                          --    C.sub.30 H.sub.28                                                             N.sub.3 O.sub.4 Na          (E-98b")                                                                            crystal                                                                             [isopro-                                                                            3.4(m, 6H), 3.15(s, 2H), 4.0-4.15                                                               1681, 1567,   C  H  N                                 panol]                                                                              (m, 1H), 4.2-5.6(m, 2H), 6.10(t,                                                                1485, 1381,   69.66                                                                            5.52                                                                             8.22                                    J = 6.7Hz, 1H), 6.57(d, J = 8.3Hz,                                                              1009          69.62                                                                            5.45                                                                             8.12                                    1H), 6.9-7.5(m, 10H), 8.29(s, 1H)                           __________________________________________________________________________

EXAMPLE 47 Methyl11-[2-(4-cinnamyl-1-piperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 20a)

Compound k, 2.0 g, obtained in Reference Example 11 and 1.2 g ofcinnamyl bromide were stirred in 100 ml of isopropanol for 4 hours atroom temperature. The mixture was extracted with 300 ml of ethylacetate. The extract was washed in succession with saturated sodiumbicarbonate aqueous solution and saturated sodium chloride aqueoussolution. After drying over anhydrous sodium sulfate, the solvent wasdistilled off under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (eluent; hexane:ethylacetate:triethylamine=10:10:1) to give 0.8 g of the objective compoundas pale yellow oil.

EXAMPLE 48 Methyl(E)-11-[3-(4-cinnamyl-1-piperazinyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound E-75a)

The objective compound was prepared using Compound s obtained inReference Example 19 and cinnamyl bromide in a manner similar to Example47.

In Examples 49 and 50 below, the objective compound was prepared byhydrolyzing esters of the corresponding oxepine derivatives and thenconverting the hydrolyzate into the fumarate in a manner similar toExample 44.

EXAMPLE 49

11-[2-(4-Cinnamyl-1-piperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid.difumarate.0.5 hydrate (Compound 20b')

EXAMPLE 50

(E)-11-[3-(4-Cinnamyl-1-piperazinyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid.difumarate.0.5 hydrate (Compound E-75b')

Physicochemical properties of the compounds obtained in Examples 47 to50 are shown in Table 7-3.

                                      TABLE 7-3                                   __________________________________________________________________________                MP (°C.)                                                   Example     [Solvent                                                          No.         for re-                                Elemental analysis                                                            (%)                        (Compound                                                                            Appear-                                                                            crystal-                                                                            NMR               IR       MS    Upper column: found        No.)   ance lization]                                                                           (solvent) δ, ppm                                                                          (method) cm.sup.-1                                                                     m/z   Lower column:              __________________________________________________________________________                                                       calcd.                     47     pale --    (CDCl.sub.3) 2.32-2.80(m, 12H), 3.14                                                            (neat)   514 (M+)                                                                              --                       (20a)  yellow     (d, J = 5.6Hz, 2H), 3.89(s, 3H),                                                                2944, 2808,                                      oil        4.89 & 6.45(ABq, J = 14.5Hz, 2H),                                                               1708, 1610,                                                 5.10(s, 1H), 6.21-8.10(m, 14H)                                                                  1571, 1497,                                                                   1007                                      48     colorless                                                                          --    (CDCl.sub.3) 2.48(m, 8H), 3.0-3.3(m,                                                            (neat)   480 (M+)                                                                              --                       (E-75a)                                                                              oil        4H), 3.81(s, 3H), 4.9-5.7(m, 2H),                                                               1715, 1606,                                                 6.05-6.5(m, 2H), 6.71(d, J = 9.2Hz,                                                             1245, 1006                                                  1H), 7.0-7.5(m, J = 9.2Hz, 9H),                                               7.73(dd, J = 2.2, 9.2Hz, 1H), 7.99                                            (d, J = 2.2Hz, 1H)                                          49     yellow                                                                             210-211                                                                             (DMSO-d.sub.6) 2.35-2.7(m, 12H), 3.25                                                           (KBr tablet)                                                                           500 (M+)                                                                            C.sub.38 H.sub.40                                                             N.sub.2 O.sub.11                                                              S.0.5H.sub.2 O             (20b') solid                                                                              [aceto-                                                                             (d, J = 6.6Hz, 2H), 5.05 & 6.25(ABq,                                                            1713, 1612,    C  H  N                                nitrile]*                                                                           J = 10.6Hz, 2H), 5.44(s, 1H), 6.25-                                                             1300, 1252,    61.48                                                                            5.42                                                                             3.88                                   6.3(m, 1H), 6.87(d, J = 8.5Hz, 1H),                                                             1170           61.53                                                                            5.57                                                                             3.78                                   7.2-7.5(m, 10H), 7.71(dd, J = 2.2,                                            8.5Hz, 1H), 7.98(d, J = 2.2Hz, 1H)                          50     white                                                                              246   (DMSO-d.sub.6) 2.4-3.3(m, 10H), 3.24                                                            (KBr tablet)                                                                           466 (M+)                                                                            C.sub.38 H.sub.38                                                             N.sub.2 O.sub.11.0.5H.s                                                       ub.2 O                     (E-75b')                                                                             crystal                                                                            (dec.)                                                                              (d, J = 6.7Hz, 2H), 4.9-5.7(m, 2H),                                                             1703, 1659,    C  H  N                                [aceto-                                                                             6.14(t, J = 6.7Hz, 1H), 6.2-6.35                                                                1605, 1250,    64.53                                                                            5.43                                                                             4.05                             nitrile]                                                                            (m, 1H), 6.82(d, J = 8.5Hz, 1H),                                                                1010, 980      64.49                                                                            5.55                                                                             3.96                                   7.2-7.55(m, 10H), 7.72(dd, J =                                                2.2, 8.5Hz, 1H), 7.90(d, J = 2.2Hz,                                           1H)                                                         __________________________________________________________________________

EXAMPLE 51 Methyl11-[2-[4-(4-fluorophenylsulfonyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 22a)

Compound k, 0.8 g, obtained in Reference Example 11 was dissolved in 50ml of pyridine and 0.5 g of 4-fluorobenzenesulfonyl chloride was addedto the solution followed by stirring at room temperature for 2 hours.The solvent was distilled off under reduced pressure. The residue wasextracted with 200 ml of ethyl acetate. The extract was washed insuccession with saturated sodium bicarbonate aqueous solution andsaturated sodium chloride aqueous solution. After drying over anhydrousmagnesium sulfate, the solvent was distilled off under reduced pressure.The obtained residue was subjected to silica gel column chromatography(eluent; hexane:ethyl acetate:triethylamine=50:20:1) to give 0.6 g ofthe crude product. The crude product obtained was recrystallized fromisopropyl ether to give 0.4 g of the objective compound.

In Examples 52 and 53 below, the objective compound was prepared usingCompound k and the corresponding sulfonyl chloride compound in a mannersimilar to Example 51.

EXAMPLE 52

Methyl11-[2-[4-(styrylsulfonyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 24a)

EXAMPLE 53

Methyl11-[2-[4-(2-thienylsulfonyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 25a)

In Examples 54 and 55 below, the objective compound was prepared usingCompound k and the corresponding acid chloride compound in a mannersimilar to Example 51.

EXAMPLE 54

Methyl11-[2-[4-(2,3,4-trimethoxybenzoyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 27a)

EXAMPLE 55

Methyl11-[2-[4-(cinnamoyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 28a)

EXAMPLE 56 Methyl11-[2-[4-(phenoxycarbonyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 30a)

Compound k, 2.0 g, obtained in Reference Example 11 was dissolved in 100ml of isopropanol and 0.75 ml of phenyl chloroformate was added to thesolution followed by stirring at room temperature for 4 hours. Thesolvent was distilled off under reduced pressure and the resultingresidue was extracted with 200 ml of ethyl acetate. The extract waswashed in succession with saturated sodium bicarbonate aqueous solutionand saturated sodium chloride aqueous solution. After drying overanhydrous magnesium sulfate, the solvent was distilled off under reducedpressure. The obtained residue was subjected to silica gel columnchromatography (eluent; hexane:ethyl acetate:triethylamine=50:30:1) togive 1.7 g of the crude product. The crude product obtained wassolidified with isopropyl ether to give 1.6 g of the objective compound.

EXAMPLE 57 Methyl11-[2-[4-(benzyloxycarbonyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 31a)

The objective compound was prepared using Compound k and benzylchloroformate in a manner similar to Example 56.

In Examples 58 and 59 below, the objective compound was prepared fromCompound s obtained in Reference Example 19 and the correspondingsulfonyl chloride compound in a manner similar to Example 51.

EXAMPLE 58

Methyl(E)-11-[2-[4-(styrylsulfonyl)-1-piperazinyl]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound E-78a)

EXAMPLE 59

Methyl(E)-11-[2-[4-(2-thienylsulfonyl)-1-piperazinyl]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound E-79a)

EXAMPLE 60 Methyl11-[2-[4-(1-naphthalenesulfonyl-1-homopiperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound 34a)

The objective compound was prepared using 1.4 g of Compound u obtainedin Reference Example 21 and 1.0 g of 1-naphthalenesulfonyl chloride in amanner similar to Example 51.

Physicochemical properties of the compounds obtained in Examples 51 to60 are shown in Table 7-4.

                                      TABLE 7-4                                   __________________________________________________________________________                 MP (°C.)                                                  Example      [Solvent                                                         No.          for re-                               Elemental analysis                                                            (%)                        (Compound                                                                            Appear-                                                                             crystal-                                                                           NMR               IR       MS    Upper column: found        No.)   ance  lization]                                                                          (solvent δ, ppm                                                                           (method) cm.sup.-1                                                                     m/z   Lower column:              __________________________________________________________________________                                                       calcd.                     51     yellow                                                                              80-82                                                                              (CDCl.sub.3) 2.25-3.15(m, 12H), 3.80                                                            (KBr tablet)                                                                           556 (M+)                                                                            C.sub.28 H.sub.29                                                             FN.sub.2 O.sub.5                                                              S.sub.2                    (22a)  amorphous                                                                           [iso-                                                                              (s, 3H), 4.85 & 6.39(ABq, J = 13.6                                                              1702, 1494,    C  H  N                                 propyl                                                                             Hz, 2H), 5.00(s, 1H), 6.77(d, J =                                                               1357, 1326,    60.60                                                                            5.39                                                                             4.88                              ether]*                                                                            8.6Hz, 1H), 6.95-8.0(m, 10H)                                                                    1244, 1172,    60.41                                                                            5.25                                                                             5.03                                                     1004                                      52     colorless                                                                           --   (CDCL.sub.3) 2.4-2.75(m, 8H), 3.15-                                                             (KBr tablet)                                                                           550 (M+)                                                                              --                       (24a)  oil        3.35(m, 4H), 3.79(s, 3H), 4.97                                                                  1715, 1607,                                                 (s, 1H), 4.82 & 6.37(ABq, J = 19.2                                                              1310, 1248,                                                 Hz, 2H), 6.7-6.85(m, 2H), 7.1-7.5                                                               1152, 1000                                                  (m, 10H), 7.71(dd, J = 3.0, 12.9Hz,                                           1H), 7.90(d, J = 3.0Hz, 1H)                                 53     yellow                                                                              80-81                                                                              (CDCl.sub.3) 2.28-3.26(m, 12H), 3.81                                                            (KBr tablet)                                                                           544 (M+)                                                                            C.sub.26 H.sub.28                                                             NO.sub.5 S.sub.3           (25a)  solid [iso-                                                                              (s, 3H), 5.00(s, 1H), 4.86 & 6.36                                                               1714, 1609,    C  H  N                                 propyl                                                                             (ABq, J = 13.2Hz, 2H), 6.68-7.98(m,                                                             1353, 1242,    57.31                                                                            5.30                                                                             5.09                              ether]*                                                                            10H)              1007           57.33                                                                            5.18                                                                             5.14                 54     colorless                                                                           --   (CDCl.sub.3) 2.15-2.75(m, 10H), 3.15-                                                           (CHCl.sub.3)                                                                           592 (M+)                                                                              --                       (27a)  oil        3.45(m, 2H), 3.8-3.9(m, 12H),                                                                   1713, 1613,                                                 5.04(s, 1H), 4.87 & 6.38(ABq, J =                                                               1461, 1295,                                                 17.1Hz, 2H), 6.62(d, J = 12.9Hz,                                                                1120, 1009                                                  1H), 6.80(d, J = 12.9H, 1H), 6.91                                             (d, J = 12.9Hz, 1H), 7.1-7.47(m,                                              4H), 7.74(dd, J = 3.0, 12.9Hz, 1H),                                           7.93(d, J = 3.0Hz, 1H)                                      55     yellow                                                                              --   (CDCl.sub.3) 2.19-2.70(m, 8H), 3.36-                                                            (KBr tablet)                                                                           528 (M+)                                                                              --                       (28a)  amorphous  3.83(m, 4H), 3.83(s, 3H), 5.03(s,                                                               1711, 1645,                                                 1H), 4.85 & 6.41(ABq, J = 12.8Hz,                                                               1606, 1245,                                                 2H), 6.61-8.06(m, 14H)                                                                          982                                       56     white 133-135                                                                            (CDCl.sub.3) 2.2-2.8(m, 8H), 3.3-3.7                                                            (KBr tablet)                                                                           518 (M+)                                                                            C.sub.29 H.sub.30                                                             N.sub.2 O.sub.5 S          (30a)  solid [iso-                                                                              (m, 4H), 3.85(s, 3H), 4.87 & 6.43                                                               1712, 1611,    C  H  N                                 propyl                                                                             (ABq, J = 12.8Hz, 2H), 5.04(s, 1H),                                                             1497, 1293,    67.00                                                                            5.90                                                                             5.12                              ether]                                                                             6.83(d, J = 8.4Hz, 1H), 6.95-7.5(m,                                                             1248, 1199,    67.16                                                                            5.83                                                                             5.40                                   9H), 7.76(dd, J = 2.4, 8.4Hz, 1H),                                                              1118                                                        7.97(d, J = 2.4Hz, 1H)                                      57     colorless                                                                           --   (CDCl.sub.3) 2.05-2.8(m, 8H), 3.4-                                                              (neat)   532 (M+)                                                                              --                       (31a)  oil        3.65(m, 4H), 3.80(s, 3H), 4.84 &                                                                2948, 1710,                                                 6.39(ABq, J = 12.6Hz, 2H), 5.02(s,                                                              1610, 1433,                                                 1H), 5.08(s, 2H), 6.81(d, J = 8.5                                                               1237, 1118,                                                 Hz, 1H), 7.0-7.5(m, 9H), 7.74                                                                   1006                                                        (dd, J = 2.4, 8.5Hz, 1H), 7.93(d,                                             J = 2.4Hz, 1H)                                              58     pale  193-196                                                                            (CDCl.sub.3) 2.45-2.9(m, 4H), 3.0-3.6                                                           (KBr tablet)                                                                           530 (M+)                                                                            C.sub.30 H.sub.30                                                             N.sub.2 O.sub.5 S          (E-78a)                                                                              yellow                                                                              [isopro-                                                                           (m, 6H), 3.91(s, 3H), 4.7-5.7(m,                                                                1715, 1607,    C  H  N                           crystal                                                                             panol]                                                                             2H), 6.23(t, J = 7.6Hz, 1H), 6.5-                                                               1310, 1248,    67.55                                                                            5.90                                                                             5.39                                   8.1(m, 14H)       1152, 1000,                                                                            67.90 5.70                                                                             5.28                                                        945                                       59     colorless                                                                           --   (CDCl.sub.3) 2.45-2.6(m, 4H), 3.0-                                                              (KBr tablet)                                                                           510 (M+)                                                                              --                       (E-79a)                                                                              oil        3.3(m, 6H), 3.86(s, 3H), 4.7-5.7                                                                1711, 1605,                                                 (m, 2H), 6.13(t, J = 6.8Hz, 1H),                                                                1351, 1241,                                                 7.0-7.65(m, 7H), 7.78(dd, J = 2.2,                                                              999                                                         8.6Hz, 1H), 6.77(d, J = 8.6Hz, 1H),                                           7.98(d, J = 2.2Hz, 1H)                                      60     colorless                                                                           --   (CDCl.sub.3) 1.6-2.0(m, 2H), 2.45-                                                              (KBr tablet)                                                                           602 (M+)                                                                              --                       (34a)  oil        2.85(m, 8H), 3.3-3.6(m, 4H), 3.86                                                               1713, 1609,                                                 (s, 3H), 4.88 & 6.43(ABq, J = 12.1                                                              1321, 1243,                                                 Hz, 2H), 4.99(s, 1H), 7.25-8.85                                                                 1005                                                        (m, 13H)                                                    __________________________________________________________________________

In Examples 61 through 63 below, the objective compound was prepared byhydrolyzing esters of the corresponding oxepine derivatives in a mannersimilar to Example 23.

EXAMPLE 61

11-[2-[4-(Styrylsulfonyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid.0.5 hydrate (Compound 24b')

EXAMPLE 62

11-[2-[4-(2-Thienylsulfonyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid.0.5 isopropanol.dihydrate (Compound 25b')

EXAMPLE 63

11-[2-[4-(2,3,4-Trimethoxybenzoyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound 27b)

EXAMPLE 6411-[2-[4-(2,3,4-Trimethoxybenzoyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid. monohydrochloride.1.1 hydrate (Compound 27b')

The objective compound was prepared as the hydrochloride from Compound27b obtained in Example 63 in a manner similar to Example 2.

In Examples 65 through 68 below, the objective compound was prepared byhydrolyzing esters of the corresponding oxepine derivatives in a mannersimilar to Example 23.

EXAMPLE 65

11-[2-[4-(Cinnamoyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound 28b)

EXAMPLE 66

11-[2-[4-(Benzyloxycarbonyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid.dihydrate (Compound 31b')

EXAMPLE 67

(E)-11-[2-[4-(Styrylsulfonyl)-1-piperazinyl]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid.0.1 isopropanol.0.1 hydrate (Compound E-78b')

EXAMPLE 68(E)-11-[2-[4-(2-Thienylsulfonyl)-1-piperazinyl]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid.0.5 hydrate (Compound E-79b')

Physicochemical properties of the compounds obtained in Examples 61 to68 are shown in Table 7-5.

                                      TABLE 7-5                                   __________________________________________________________________________                 MP (°C.)                                                  Example      [Solvent                                                         No.          for re-                               Elemental analysis                                                            (%)                        (Compound                                                                            Appear-                                                                             crystal-                                                                           NMR               IR       MS    Upper column: found        No.)   ance  lization]                                                                          (solvent) δ, ppm                                                                          (method) cm.sup.-1                                                                     m/z   Lower column:              __________________________________________________________________________                                                       calcd.                     61     white 232-235                                                                            (DMSO-d.sub.6) 2.3-2.7(m, 8H), 3.0-                                                             (KBr tablet)                                                                           --    C.sub.29 H.sub.30                                                             N.sub.2 O.sub.5                                                               S.sub.2.0.5H.sub.2 O       (24b') crystal                                                                             [isopro-                                                                           3.3(m, 4H), 5.44(s, 1H), 5.10 &                                                                 1685, 1603,    C  H  N                                 panol]                                                                             6.31(ABq, J = 19.2Hz, 2H), 6.86(d,                                                              1313, 1246,    62.30                                                                            5.63                                                                             4.82                                   J = 13.5Hz, 1H), 7.25-7.65(m, 10H),                                                             1157, 1002,    62.23                                                                            5.58                                                                             5.00                                   7.65-7.9(m, 2H), 7.98(d, J = 3.0Hz,                                                             957                                                         1H)                                                         62     white 167-168                                                                            (DMSO-d.sub.6) 2.50-3.46(m, 12H),                                                               (KBr tablet)                                                                           530 (M+)                                                                            C.sub.25 H.sub.26                                                             N.sub.2 O.sub.5                                                               S.sub.3.0.5                (25b') crystal                                                                             [isopro-                                                                           5.05 & 6.17(ABq, J = 12.7Hz, 2H),                                                               3400, 2860,    C.sub.3 H.sub.8                                                               O.2H.sub.2 O                            panol]                                                                             5.47(s, 1H), 6.86-8.11(m, 10H),                                                                 1687, 1607,    C  H  N                                      12.76(bs, 1H)     1354, 1159     53.53                                                                            5.20                                                                             4.55                                                                    53.34                                                                            5.41                                                                             4.69                 63     pale  --   (DMSO-d.sub.6) 2.85-3.65(m, 12H),                                                                 --     578 (M+)                                                                              --                       (27b)  yellow     3.75-3.85(m, 9H), 5.52(s, 1H),                                     amorphous  5.09 & 6.15(ABq, J = 12.9Hz, 2H),                                             6.85-7.00(m, 3H), 7.4-7.5(m, 4H),                                             7.73(dd, J = 2.1, 8.6Hz, 1H),                                                 8.04(d, J = 2.1Hz, 1H)                                      64     white 165-168                                                                              --              (KBr tablet)                                                                           --    C.sub.31 H.sub.34                                                             N.sub.2 O.sub.7                                                               S.HCl.1H.sub.2 O           (27b') crystal                                                                             [iso-                  2934, 1583,    C  H  N                                 propyl                 1462, 1227,    58.63                                                                            6.23                                                                             4.23                              ether                  1011           58.64                                                                            5.90                                                                             4.41                 65     white 218-219                                                                            (DMSO-d.sub.6) 2.25-3.75(m, 12H),                                                               (KBr tablet)                                                                           514 (M+)                                                                            C.sub.30 H.sub.30                                                             N.sub.2 O.sub.4 S          (28b)  crystal                                                                             [isopro-                                                                           5.05 & 6.28(ABq, J = 12.5Hz, 2H),                                                               1692, 1642,    C  H  N                                 panol]                                                                             5.45(s, 1H), 6.87(d, J = 8.5Hz,                                                                 1566, 1227,    69.91                                                                            5.96                                                                             5.39                                   1H), 7.24(d, J = 15.5Hz, 1H), 7.3-                                                              1004, 987      70.02                                                                            5.88                                                                             5.44                                   7.5(m, 5H), 7.48(d, J = 15.5Hz,                                               1H), 7.65-7.8(m, 3H), 8.00(d, J =                                             2.1Hz, 1H)                                                  66     white 207-208                                                                            (DMSO-d.sub.6) 2.8-4.2(m, 12H), 5.12                                                            (KBr tablet)                                                                           518 (M+)                                                                            C.sub.29 H.sub.30                                                             N.sub.2 O.sub.5                                                               S.2H.sub.2 O               (31b') crystal                                                                             [toluene]                                                                          (s, 2H), 5.09 & 6.15(ABq, J =  12.9                                                             1714, 1677,    C  H  N                                      Hz, 2H), 5.52(s, 1H), 6.90(d, J =                                                               1611, 1436,    62.43                                                                            6.51                                                                             4.96                                   8.6Hz, 1H), 7.3-7.6(m, 9H), 7.73                                                                1200, 1161,    62.80                                                                            6.18                                                                             5.05                                   (dd, J = 2.2, 8.6Hz, 1H), 8.04(d,                                                               1005                                                        J = 2.2Hz, 1H), 11.25(bs, 1H)                               67     white 233-235                                                                            (DMSO-d.sub.6) 2.2-3.5(m, 10H), 5.00                                                            (KBr tablet)                                                                           516 (M+)                                                                            C.sub.29 H.sub.28                                                             N.sub.2 O.sub.5 S.         (E-78b')                                                                             crystal                                                                             (dec.)                                                                             & 5.52(each bs, 2H), 6.10(t, J =                                                                1685, 1603,    0.5H.sub.2 O.0.1C.sub.3                                                        H.sub.8 O                              [isopro-                                                                           6.6Hz, 1H), 6.83(d, J = 8.5Hz, 1H),                                                             1570, 1348,    C  H  N                                 panol]                                                                             7.2-7.9(m, 11H)   1313, 1246,    66.37                                                                            5.70                                                                             5.11                                                     1002, 957      66.20                                                                            5.65                                                                             5.27                 68     white 250-251                                                                            (DMSO-d.sub.6) 2.3-3.5(m, 10H), 4.99                                                            (KBr tablet)                                                                            496 (M+)                                                                           C.sub.25 H.sub.24                                                             N.sub.2 O.sub.5                                                               S.sub.2.0.5H.sub.2 O       (E-79b')                                                                             crystal                                                                             (dec.)                                                                             & 5.50(each bs, 2H), 6.07(bs,                                                                   1685, 1607,    C  H  N                                 [isopro-                                                                           1H), 6.82(d, J = 8.5Hz, 1H), 7.2-                                                               1353, 1316,    59.33                                                                            4.74                                                                             5.47                              panol]                                                                             7.65(m, 6H), 7.71(dd, J = 2.2, 8.5                                                              1246, 1166,    59.39                                                                            4.98                                                                             5.54                                   Hz, 1H), 7.87(d, J = 2.2Hz, 1H),                                                                1009, 954                                                   8.05-8.10(m, 1H)                                            __________________________________________________________________________

PHAARMACEUTICAL PREPARATION 1 Tablet

A tablet having the following composition is prepared in a conventionalmanner.

    ______________________________________                                        Compound 1b'           100    mg                                              Lactose                60     mg                                              Potato starch          30     mg                                              Polyvinyl alcohol      2      mg                                              Magnesium stearate     1      mg                                              Tar pigment            trace                                                  ______________________________________                                    

PHARMACEUTICAL PREPARATION 2 Powder

Powders having the following composition are prepared in a conventionalmanner.

    ______________________________________                                        Compound 38b'   100 mg                                                        Lactose         300 mg                                                        ______________________________________                                    

PHARMACEUTICAL PREPARATION 3 Syrup

Syrup having the following composition is prepared in a conventionalmanner.

    ______________________________________                                        Compound 38b'           100    mg                                             Refined sugar           30     g                                              Ethyl p-hydroxybenzoate 40     mg                                             Propyl p-hydroxybenzoate                                                                              10     mg                                             Strawberry flavor       0.1    cc                                             Water is added until the whole volume is 100 cc.                              ______________________________________                                    

PHARMACEUTICAL PREPARATION 4 Tablet

A tablet having the following composition is prepared in a conventionalmanner.

    ______________________________________                                        Compound E-78b'        100    mg                                              Lactose                60     mg                                              Potato starch          30     mg                                              Polyvinyl alcohol      2      mg                                              Magnesium stearate     1      mg                                              Tar pigment            trace                                                  ______________________________________                                    

PHARMACEUTICAL PREPARATION 5 Syrup

Syrup having the following composition is prepared in a conventionalmanner.

    ______________________________________                                        Compound E-78b'         100    mg                                             Refined sugar           30     g                                              Ethyl p-hydroxybenzoate 40     mg                                             Propyl p-hydroxybenzoate                                                                              10     mg                                             Strawberry flavor       0.1    cc                                             Water is added until the whole volume is 100 cc.                              ______________________________________                                    

While the invention has been described in detail and with reference tospecific embodiments thereof, it will be apparent to one skilled in theart that various changes and modifications can be made therein withoutdeparting from the spirit and scope thereof.

What is claimed is:
 1. A tricyclic compound represented by formula (I):##STR136## wherein represents single or double bond;X₁ -X₂ represents--CH₂ O--; W represents --S-- or ═CH--; n is 1, 2, 3, or 4; one of R^(A)and R^(B) represents hydrogen and the other represents --Y--M wherein Yrepresents single bond, --CR¹ R² (CH₂)_(m) --, --CR¹ ═CR² --(CH₂)_(m)--, wherein each of R¹ and R² independently represents hydrogen or loweralkyl and m is 0, 1, 2, 3 or 4, in which the left side of each formulais bound to the mother nucleus; and M represents --COOR³ wherein R³represents hydrogen or lower alkyl, CONR^(3a) R^(3b) herein each ofR^(3a) and R^(3b) independently has the same significances for R³ asdescribed above, or tetrazoyl; each of G^(A) and G^(B) independentlyrepresents lower alkyl, halogen, hydroxyl, or lower alkoxyl; each ofg^(a) and g^(b) independently represents 0, 1, 2 or 3; Z represents>N--E¹ --Q, wherein E¹ represents single bond, --CO--, --COO-- whereinthe left side of the formula is bound to the nitrogen atom, or --SO₂ --;and Q represents optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, aromatic heterocyclic groupor ##STR137## p is 2; and pharmaceutically acceptable salts thereof. 2.A compound according to claim 1, wherein one of R^(A) and R^(B)represents hydrogen and the other represents --Y--COOH.
 3. A compoundaccording to claim 2, wherein Y is a member selected from the groupconsisting of single bond, ##STR138##
 4. A compound according to claim3, wherein n is 2 and W represents --S--.
 5. A compound according toclaim 3, wherein n is 1 or 2 and W represents ═CH--.
 6. A compoundaccording to 4 or 5, wherein Q represents optionally substituted arylhaving 6 to 10 carbon atoms, optionally substituted aralkyl having 7 to20 carbon atoms or optinally substituted aralkenyl having 8 to 18 carbonatoms.
 7. A compound according to claim 6, the optional substitutent onthe aryl, aralkyl or aralkenyl means 1 to 3 substituents on the aromaticring and the substituent(s) is/are independently selected from the groupconsisting of lower alkyl, halogen, trifluoromethyl, hydroxyl, loweralkoxyl and methylenedioxy formed together with the orthoposition of thearomatic ring.
 8. A compound according to claim 4 or 5, wherein Qrepresents the aromatic heterocyclic group selected from the groupconsisting of furyl, thienyl, pyridyl, pyrimidinyl, quinolyl andisoquinolyl.
 9. A compound according to any one of claims 4 and 5,wherein E¹ represents single bond or --SO₂ --, Q is selected from thegroup consisting of optionally substituted phenyl, optionallysubstituted benzyl, optionally substituted benzhydryl, phenethyl,styryl, cinnamyl, thienyl and ##STR139##
 10. A compound according toclaim 9, which is selected from the group consistingof11-[2-(4-phenyl-1-piperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid,11-[2-[4-(4-fluorophenyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid,11-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid,11-[2-(4-benzyl-1-piperazinyl)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid,11-[2-[4-(2-thienylsulfonyl)-1-piperazinyl]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid,11-[3-(4-benzyl-1-piperazinyl)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid,11-[2-[4-(4-fluorophenyl)piperazinyl]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid,11-[2-(4-cinnamyl-1-piperazinyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid,11-[2-[4-(styrylsulfonyl)-1-piperazinyl]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid and11-[2-[4-(2-thienylsulfonyl)-1-piperazinyl]ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid.
 11. A compound according to claim 1, wherein said salt is selectedfrom the group consisting of acid addition salt, metal salt, ammoniumsalt, organic amine addition salt and amino acid addition salt.
 12. Apharmaceutical composition comprising a pharmaceutical carrier and, asan active ingredient, an effective amount of a tricyclic compound asdefined by claim 1.